Extruded Immediate Release Abuse Deterrent Pill

ABSTRACT

The present disclosure relates to an oral, immediate release, abuse deterrent pill containing at least one active pharmaceutical ingredient susceptible to abuse which is homogenously spread throughout a carrier matrix used to deter abuse. The pill is prepared using hot melt extrusion and a forming unit through a continuous process. The formed pill is abuse deterrent to parenteral administration due at least to particle size, viscosity, or purity limitations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/457,714, filed on Aug. 12, 2014, which claims priority under35 U.S.C. § 119(e) to U.S. Provisional Application No. 61/864,926, filedon Aug. 12, 2013, and 61/980,242, filed on Apr. 16, 2014, the entirecontents of each of the above-referenced applications are incorporatedherein by reference.

FIELD OF THE TECHNOLOGY

The present disclosure relates to an oral immediate release, abusedeterrent pill prepared using a hot melt extrusion process and a formingunit. The pill contains at least one abuse deterrent mechanism to reduceabuse by non-oral administration routes, e.g. intranasal and/orintravenous. The extrusion process and forming unit are designed toefficiently prepare the abuse deterrent pill under conditions thatreduce, or substantially eliminate, degradation of the active substance.

BACKGROUND OF THE INVENTION

FDA-approved drugs are provided in many different forms based on thetype of active substance, the indication treated and the preferred routeof administration. These forms include enteral formulations (e.g.,tablets, capsules or pills), parenteral formulations (e.g., injectableformulations such as intravenous, subcutaneous, intramuscular andintraarticular), liquid formulations (e.g., elixirs), lyophilizedformulations and topical formulations. A majority of the FDA-approveddrugs are currently available in enteral form, as either a tablet orcapsule.

The production of pharmaceutical drugs in pill form by hot meltextrusion is relatively uncommon. While the idea of dissolving drugs inpolymers and using extrusion to produce a pill has been known fordecades, only a handful of FDA-approved drugs are extruded. Recently,extrusion techniques have been investigated for preparing abusedeterrent formulations. For example, U.S. Pat. No. 8,075,872 (assignedto Grunenthal GmbH) is directed to a thermoshaped abuse deterrent dosageform prepared with the assistance of an extruder. The extrudate may beshaped by the assistance of contra-rotating calendar rolls, andsingulated by conventional means such as chopping. U.S. Pat. No.8,383,152 (assigned to Grunenthal GmbH) is directed to a controlledrelease pharmaceutical dosage form that may also be prepared byextrusion and shaped by a calendaring process. U.S. 2007/0190142(assigned to Abbott GmbH) is directed to a sustained release abusedeterrent dosage form prepared by extrusion and shaping the extrudateinto a dosage form without a milling or multi-particulating step.

SUMMARY OF THE INVENTION

The present disclosure relates to an abuse deterrent pill prepared usinga hot melt extrusion process and a forming unit. The formulationcontains an active substance susceptible to abuse and at least one abusedeterrent mechanism to reduce abuse by non-oral administration routes(e.g., intranasal and/or intravenous). The abuse deterrent pill isdesigned for immediate release of the active substance upon oraladministration. The method of preparing the pill utilizes a hot meltextrusion process coupled with an in-line forming unit which eliminatesthe need for traditional extrusion processing steps, such as choppingthe extrudate and molding the cut extrudate into a final form. The hotmelt extrusion process and forming unit are operated under conditionsthat reduce, or substantially eliminate degradation of the activesubstance.

In one embodiment, the present disclosure relates to a directly-formedoral, extruded, immediate release, abuse deterrent pill comprising anactive substance susceptible to abuse, a matrix agent and a plasticizer,wherein the pill is directly formed from a hot melt extrusion process,preferably without further processing (e.g., a cutting step). Theextrudate may be re-sized or re-shaped, without cutting, prior toforming (e.g., rope sizer).

In another embodiment, the present disclosure relates to an oral,immediate release, abuse deterrent pill comprising an active substancesusceptible to abuse, a matrix agent and a plasticizer, wherein theactive substance susceptible to abuse has an immediate release profile,and wherein the composition includes a physical barrier to reduce abuse.In some embodiments, the physical barrier can reduce abuse by techniquessuch as pulverizing and swallowing, pulverizing and snorting, orpulverizing and injecting. In other embodiments, the physical barriercan reduce abuse by forming a hydrogel upon exposure to an aqueous orsemi-aqueous solution. In some embodiments, the semi-aqueous solution isa 95% ethanol/5% water solution.

In another embodiment, the present disclosure relates to a process forthe production of an oral, immediate release, abuse deterrent pillcontaining at least one active substance susceptible to abuse comprisingprocessing a uniform blend of the at least one active substancesusceptible to abuse, a matrix agent and a plasticizer by hot meltextrusion to form an extrudate. The extrudate may therein be formed intothe pill using a forming unit.

In another embodiment, the present disclosure relates to a process forthe production of an oral, immediate release, abuse deterrent pillcontaining at least one active substance susceptible to abuse comprisingone or more of the following steps: combining the at least one activesubstance susceptible to abuse, a matrix agent and a plasticizer in ahopper to form a mixture; blending the mixture in the hopper until auniform blend is achieved; monitoring the mixture during blending usinga process analytical technique to determine when a uniform blend isachieved; feeding the uniform blend into an extruder; processing theuniform blend by hot melt extrusion to produce an extrudate;transferring the extrudate to a forming unit using a transfer unitcapable of controlling the temperature, pressure, environment and/orshape of the extrudate; forming the extrudate using the forming unitinto the pill; and determining the quality, volume and weight of thepill using an optical inspection technique.

In another embodiment, the present disclosure relates to a method oftreating pain comprising administering to an individual in need thereofa therapeutically effective amount of an abuse deterrent formulationprepared using a hot melt extrusion process and a forming unit asdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an embodiment of the extruder (14) and forming unit (60).The extruder has multiple temperature zones (e.g., 20-30) and pressurezones (e.g., 20, 40-43) to control the formation of a uniform extrudateunder conditions that reduce, or substantially eliminate, degradation ofthe active substance.

FIG. 2 shows an embodiment of a chain forming unit. The chain formingunit includes an upper and lower chain system (110 and 112) and tooling(100) to form the incoming extrudate (56) into formed pills (19).

FIG. 3 shows an embodiment of an extrudate sizing apparatus (e.g., ropesizer). The rope sizer includes consecutive rollers (90-96) rotating atconsecutively faster speeds for accepting an incoming extrudate (52) andexpelling a faster moving, re-sized (smaller diameter) extrudate (54).

FIG. 4 shows the percent release of the active substance (i.e.,acetaminophen dissolution in 45 minutes) versus the weight percent ofthe matrix agent (e.g., polyethylene oxide or PEO) for two similar abusedeterrent pill formulations having different molecular weight matrixagents (e.g., 300K Daltons PEO vs. 600K Daltons PEO).

FIG. 5 shows the weight percent of particles formed by grinding whichhave a particle size less than 0.5 mm versus the weight percent ofmatrix agent (e.g., PEO). The particles are formed by grinding theformulation in a commercial coffee grinder for at least 30 seconds.

FIG. 6 shows equipment capable of executing traditional “tablet breakingforce” analysis.

FIG. 7 shows equipment capable of executing a “cutting force” analysisincluding a top view of a fracture wedge set attachment used to mimiccommon kitchen scissors.

FIG. 8 shows a side view of the fracture wedge set attachment of FIG. 7.

FIG. 9 shows equipment capable of executing a “cutting force” analysisincluding a razor blade attachment.

FIGS. 10A and 10B show cutting force data tables for the razor blade andthe fracture wedge attachments.

FIGS. 11A and 11B show particle size analyses for exemplary formulationsdescribed in the present disclosure.

FIGS. 12A, 12B, 12C, 12D, 12E and 12F show grinding results forexemplary formulations described in the present disclosure.

FIG. 13 shows the results of the dissolution, purity and dye evaluationtests on exemplary formulations.

FIG. 14 shows a representation of particle size results (%≥500 μm) whencomparing the tested Immediate Release (IR) Roxicodone® batch vs. theformulations of the present disclosure (e.g., IR batches) utilizing bothTE96 and the Mr. Coffee grinder.

FIG. 15 shows a representation of particle size results (%≥500 μm) whencomparing the tested Extended Release (ER) CII narcotic drug productsbetween manufacturers.

DETAILED DESCRIPTION

Abuse of prescription drugs, particularly opioids, is a serious andgrowing public health concern. To address this concern, new formulationsare being developed that contain abuse-deterrent properties. Abusedeterrent properties include properties that make product manipulationmore difficult or make abuse of the manipulated product less attractiveor rewarding.

Recently the FDA issued a draft guidance for industry related toformulations having abuse deterrent properties. Guidance for Industry:Abuse Deterrent Opioids—Evaluation and Labeling, U.S. Department ofHealth and Human Services, FDA, CDER, January 2013, the entire contentsof which are incorporated herein by reference. These guidelines separateabuse deterrent formulations into six categories, including:physical/chemical barriers, agonist/antagonist combinations, aversion,delivery system, prodrug, or a combination of the aforementioned. Asdescribed by the FDA guidance, the categories are:

Physical/Chemical barriers—Physical barriers can prevent chewing,pulverizing, cutting, grating, or grinding. Chemical barriers can resistextraction of the opioid using common solvents like water, alcohol, orother organic solvents. Physical and chemical barriers can change thephysical form of an oral drug rendering it less amenable to abuse.

Agonist/Antagonist combinations—An opioid antagonist can be added tointerfere with, reduce, or defeat the euphoria associated with abuse.The antagonist can be sequestered and released only upon manipulation ofthe product. For example, a drug product may be formulated such that thesubstance that acts as an antagonist is not clinically active when theproduct is swallowed but becomes active if the product is crushed andinjected or snorted.

Aversion—Substances can be combined to produce an unpleasant effect ifthe dosage form is manipulated prior to ingestion or a higher dosagethan directed is used.

Delivery System (including depot injectable formulations andimplants)—Certain drug release designs or the method of drug deliverycan offer resistance to abuse. For example, a sustained-release depotinjectable formulation that is administered intramuscularly or asubcutaneous implant can be more difficult to manipulate.

Prodrug—A prodrug that lacks opioid activity until transformed in thegastrointestinal tract can be unattractive for intravenous injection orintranasal routes of abuse.

Combination—Two or more of the above methods can be combined to deterabuse.

An opioid analgesic submitted for abuse deterrent formulation (ADF)labeling must show conformance to one or more of these categories. Thepresent disclosure relates to an abuse deterrent pill for oraladministration, which provides immediate release of an activepharmaceutical substance and conforms to one or more of thesecategories. In one embodiment, the abuse deterrent formulation of thepresent disclosure conforms to at least one of the six FDA categories.In another embodiment, the abuse deterrent formulation of the presentdisclosure conforms to at least two of the six FDA categories. Inanother embodiment, the abuse deterrent formulation of the presentdisclosure conforms to at least three of the six FDA categories. Inanother embodiment, the abuse deterrent formulation of the presentdisclosure conforms to at least four of the six FDA categories. Inanother embodiment, the abuse deterrent formulation of the presentdisclosure conforms to at least five of the six FDA categories.

For example, an abuse deterrent pill of the present disclosure canreduce abuse by the incorporation of at least one physical barrier. Thephysical barrier is designed to prevent abuse based on chewing,pulverizing, cutting, grating or grinding. Preferably, the physicalbarrier prevents or reduces the effectiveness of these methods. As usedherein, the phrase “abuse deterrent” means that the active substancecannot readily be separated from the formulation in a form suitable forabuse by such means as, for example, grinding. The abuse deterrent pillof the present disclosure cannot be easily ground, extracted from, orboth. Abuse deterrent measures render it difficult to transform the pillinto a powder or extract for non-oral administration, such as intranasalor intravenous.

In one embodiment, the present disclosure relates to a directly-formed,extruded, oral, immediate release, abuse deterrent pill. The pillincludes an active substance susceptible to abuse, a matrix agent and aplasticizer. After extrusion, the extrudate is directly formed into thepill without further processing, such as the use of a cutting step.

As used herein, the term “active substance” or “active substancesusceptible to abuse” means an opioid or opioid related compound subjectto potential abuse. The active substance may include, withoutlimitation, alfentanil, allylprodine, alphaprodine, amphetamine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextroamphetamine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levophenacylmorphan, levorphanol, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,nalbulphine, narceine, nicomorphine, norpipanone, opium, oxycodone,papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan,phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tilidine,and tramadol, and pharmaceutically acceptable salts and mixturesthereof. Preferably, the active substance is either oxycodone orhydrocodone. In one embodiment, the formulation of the presentdisclosure excludes oxymorphone. For example, the formulation of thepresent disclosure contains at least one active substance susceptible toabuse, provided the active substance is not oxymorphone.

The amount of active substance in the formulation may vary depending onthe active substance, stability, release profile and bioavailability.The amount of active substance in the formulation may range from about0.50 Wt % to about 15 Wt %. Particularly, the amount of active substancein the formulation may range from about 0.75 Wt % to about 14 Wt %, orfrom about 1.0 Wt % to about 13 Wt %, or from about 2.0 Wt % to about 12Wt %, or from about 3.0 Wt % to about 11 Wt %, or from about 5.0 Wt % toabout 10 Wt %. For example, the formulation may be a 100 mg pill havingabout 5 mg or about 10 mg of active substance (e.g., oxycodone HCl orhydrocodone bitartrate).

In another embodiment, the amount of active substance in the formulationmay range from about 0.50 Wt % to about 40 Wt %. Particularly, theamount of active substance in the formulation may range from about 0.75Wt % to about 37.5 Wt %, or from about 1.0 Wt % to about 35 Wt %, orfrom about 2.0 Wt % to about 34 Wt %, or from about 3.0 Wt % to about32.5 Wt %, or from about 5.0 Wt % to about 30 Wt %. For example, theformulation may be a 100 mg pill having about 5 mg or about 30 mg ofactive substance (e.g., oxycodone HCl or hydrocodone bitartrate).

Formulations of the present disclosure may also include an additionalactive ingredient. Additional active ingredients include otheranalgesics, such as acetaminophen, ibuprofen, acetylsalicylic acidand/or naproxen. For example, the formulation may include an oxycodoneHCl/acetaminophen combination, or a hydrocodone bitartrate/acetaminophencombination.

In one embodiment, the formulation includes at least one activesubstance, e.g. hydrocodone bitartrate, and at least one additionalingredient, e.g. acetaminophen. The amount of the at least one activesubstance and the additional ingredient in the formulation may varydepending on the active substance or the additional ingredient, theirstability, their release profile and their bioavailability. In additionto the ranges provided above for the amount of active substance in theformulation, the amount of active substance in the formulation may alsorange from about 0.10 Wt % to about 10.0 Wt %. Particularly, the amountof active substance in the formulation may range from about 0.20 Wt % toabout 8.0 Wt %, or from about 0.3 Wt % to about 6.0 Wt %, or from about0.4 Wt % to about 4.0 Wt %, or from about 0.5 Wt % to about 2.0 Wt %.The amount of additional ingredient in the formulation may range fromabout 15 Wt % to about 80 Wt %. Particularly, the amount of additionalsubstance in the formulation may range from about 20 Wt % to about 75 Wt%, or from about 25 Wt % to about 70 Wt %, or from about 30 Wt % toabout 65 Wt %. For example, the formulation may be a 500 mg or 1,000 mgpill having about 5 mg or about 10 mg of active substance (e.g.,oxycodone HCl or hydrocodone bitartrate) and about 300 mg or about 325mg of additional analgesic (e.g. acetaminophen).

The dosage form of the present disclosure can be rendered abusedeterrent by incorporating at least one matrix agent in the formulationto increase the strength of the tablet beyond that of conventionaldosage forms. The matrix agent increases the dosage form's resistance tophysical or mechanical forces, such as pulverizing or grinding. Byselecting the appropriate molecular weight grade and the quantitypresent within a formulation, the strength characteristics of the dosageform can be manipulated in a way to create a wide array of abusedeterrent pills have immediate release profiles.

The matrix agent may also render the dosage form abuse deterrent byacting as a gelling or viscosity increasing agent. Upon contact with asolvent (e.g., aqueous or semi-aqueous solution), the dosage form iscapable of absorbing the solvent and swelling to form a viscous orsemi-viscous substance. The formation of a viscous or semi-viscoussubstance significantly reduces and/or minimizes the amount of freesolvent which can contain an amount of active substance, and which canbe drawn into a syringe. The matrix agent can also reduce the overallamount of active substance extractable with the solvent by entrappingthe active substance in a gel matrix. Typical matrix agents includepharmaceutically acceptable polymers, typically hydrophilic polymers,such as those that form hydrogels. These properties allow for an oraldrug delivery system that satisfies at least one of the categories inthe FDA guidance (e.g., “physical and chemical barriers can change thephysical form of an oral drug rendering it less amenable to abuse”).

The matrix agent may exhibit a high degree of viscosity upon contactwith a suitable solvent. The high viscosity can enhance the formation ofhighly viscous gels when attempts are made to crush and dissolve thecontents of a formulation in an aqueous or semi-aqueous vehicle andinject it intravenously. For example, when an abuser crushes anddissolves the formulation in a solvent, a viscous or semi-viscous gel isformed. The increase in the viscosity of the solution discourages theabuser from injecting the gel intravenously or intramuscularly bypreventing the abuser from transferring sufficient amounts of thesolution to a syringe.

Suitable matrix agents are natural or synthetic polymers capable ofproviding increased resistance to pulverizing or grinding. The matrixagent may be selected from the group consisting of agar, alamic acid,alginic acid, carmellose, carboxymethylcellulose sodium, chitosan,copovidone, dextrin, gelatin, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose (HPMC), methylcellulose derivatives,microcrystalline cellulose, polyacrylic acid, polyalkalene oxide (e.g.,polymethylene oxide, polyethylene oxide and polypropylene oxide),polyvinyl acetate, polyvinyl alcohol, povidone, propylene glycolalginate, polyvinylcaprolactam—polyvinyl acetate—polyethylene glycolgraft co-polymer, pullulan, silicon dioxide, sodium alginate, starch,and vinylpyrrolidone-vinyl acetate copolymers. In one embodiment, thematrix agent is a polyethylene oxide. Polyethylene oxide is a non-ionic,water soluble polymer that is readily available in a wide range ofmolecular weight grades.

The matrix agent should be capable of both ensuring the formation of asolid dosage form by extrusion and allowing immediate release of theactive substance. The formulation of the present disclosure mayaccomplish both capabilities by using a matrix agent having anappropriate molecular weight (or appropriate average molecular weight),such as between about 50K Daltons and about 300K Daltons.

In one embodiment, the matrix agent has a molecular weight between about100K and about 300K Daltons. Particularly, the matrix agent has amolecular weight between about 150K and about 250K Daltons, or about180K and about 220K Daltons, or about 190K and about 210K Daltons, orabout 195K and about 205K Daltons.

In another embodiment, the matrix agent has a molecular weight betweenabout 100K and about 200K Daltons. Particularly, the matrix agent has amolecular weight between about 120K and about 180K Daltons, or about130K and about 170K Daltons, or about 140K and about 160K Daltons, orabout 145K and about 155K Daltons.

In another embodiment, the matrix agent has a molecular weight betweenabout 50K and about 150K Daltons. Particularly, the matrix agent has amolecular weight between about 80K and about 120K Daltons, or about 85Kand about 115K Daltons, or about 90K and about 110K Daltons, or about95K and about 105K Daltons.

In another embodiment, the matrix agent has a molecular weight betweenabout 50K and about 100K Daltons. Particularly, the matrix agent has amolecular weight between about 55K and about 95K Daltons, or about 60Kand about 90K Daltons, or about 65K and about 85K Daltons, or about 70Kand about 80K Daltons.

The performance of the matrix agent and the formulation is alsodependent on the amount of matrix agent present in the formulation. Theformulation, or final dosage form, may contain about 10 Wt % to about 90Wt % matrix agent.

In one embodiment, the formulation contains between about 40 Wt % and 60Wt % matrix agent. Particularly, the formulation contains between about45 Wt % and about 55 Wt % matrix agent, or about 48 Wt % and about 52 Wt% matrix agent.

In another embodiment, the formulation contains between about 35 Wt %and 55 Wt % matrix agent. Particularly, the formulation contains betweenabout 40 Wt % and about 50 Wt % matrix agent, or about 43 Wt % and about47 Wt % matrix agent.

In another embodiment, the formulation contains between about 30 Wt %and 50 Wt % matrix agent. Particularly, the formulation contains betweenabout 35 Wt % and about 45 Wt % matrix agent, or about 38 Wt % and about42 Wt % matrix agent.

In another embodiment, the formulation contains between about 25 Wt %and 45 Wt % matrix agent. Particularly, the formulation contains betweenabout 30 Wt % and about 40 Wt % matrix agent, or about 33 Wt % and about37 Wt % matrix agent.

In another embodiment, the formulation contains between about 20 Wt %and 40 Wt % matrix agent. Particularly, the formulation contains betweenabout 25 Wt % and about 35 Wt % matrix agent, or about 28 Wt % and about32 Wt % matrix agent.

In another embodiment, the formulation contains between about 15 Wt %and 35 Wt % matrix agent. Particularly, the formulation contains betweenabout 20 Wt % and about 30 Wt % matrix agent, or about 23 Wt % and about27 Wt % matrix agent.

The dosage form of the present disclosure can also be rendered abusedeterrent by incorporating at least one plasticizer in the formulation.The plasticizer may provide the dosage form with a waxiness uponexposure to physical or mechanical forces, such as pulverizing orgrinding. Suitable plasticizers may be selected from the groupconsisting of polyalkalene glycols (e.g., polyethylene glycol andpolyethylene glycol monomethyl ether), acetyltributyl citrate,acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutylsebacate, diethyl phthalate, glycerin, propylene glycol, pullulan,sorbitol sorbitan solution, triacetin, tributyl citrate and triethylcitrate. In one embodiment, the plasticizer is polyethylene glycol.

The performance of the plasticizer is dependent on the size and theamount of plasticizer present in the formulation. In one embodiment, theplasticizer cannot be filtered and/or separated from a resultingsolution of water and/or alcohol. The formulation of the presentdisclosure may include a plasticizer having a molecular weight betweenabout 1K Daltons and about 15K Daltons. Particularly, the molecularweight is between about 2K Daltons and about 14K, about 3K and about 13KDaltons, about 5K and about 10K Daltons, or about 7K and about 9KDaltons.

The formulation, or final dosage form, may contain between about 5.0 Wt% and about 60 Wt % plasticizer. In one embodiment, the formulationcontains between about 20 Wt % and about 60 Wt % plasticizer.Particularly, the formulation contains between about 30 Wt % and about50 Wt % plasticizer, or about 35 Wt % and about 45 Wt % plasticizer. Inanother embodiment, the formulation contains between about 15 Wt % andabout 30 Wt % plasticizer. Particularly, the formulation containsbetween about 20 Wt % and about 28 Wt % plasticizer, or about 23 Wt %and about 27 Wt % plasticizer. In another embodiment, the formulationcontains between about 5.0 Wt % and about 20 Wt % plasticizer.Particularly, the formulation contains between about 8.0 Wt % and about17 Wt % plasticizer, or about 10 Wt % and about 15 Wt % plasticizer.

The dosage form of the present disclosure may also contain afiller/binder excipient (herein “filler”). A filler may be added toprovide or increase the consistency of the extrudate for processing intoa final dosage form. The filler may also help with hardness anddissolution of the dosage form. The filler may be a known excipient foruse in pharmaceutical formulations that, upon extrusion, is capable ofproducing an extrudate that holds its shape. In some embodiments, thefiller may have a melting temperature above the extrusion processtemperatures, such as a melting temperature above about 80° C., 90° C.,100° C., 110° C., 120° C., or 130° C. The filler may also be a materialthat exhibits excellent flow and compression properties, wherein suchflow and compression properties are measured by traditional methodsknown to persons skilled in the art of pharmaceutical formulations.

The filler may be selected from the group consisting of microcrystallinecellulose, silicified microcrystalline cellulose, powdered cellulose,maize starch, modified maize starch, potato starch, lactose monohydrate,lactose anhydrous, mannitol, dibasic calcium phosphate dihydrate,anhydrous dibasic calcium phosphate, magnesium carbonate, erythritol,trehalose and mixtures thereof. In one embodiment, the filler ismicrocrystalline cellulose and/or lactose monohydrate.

In some embodiments, the filler may also be useful as a disintegrant.For example, the inclusion of 10% or more of a filler, e.g.,microcrystalline cellulose, also acts as a disintegrant.

The performance of the filler and the formulation is also dependent onthe amount of filler present in the formulation. The formulation, orfinal dosage form, may contain between about 0 Wt % and about 40 Wt %filler. In one embodiment, the formulation contains between about 10 Wt% and about 40 Wt % filler. Particularly, the formulation containsbetween about 20 Wt % and about 40 Wt % filler, about 30 Wt % and about40 Wt % filler, about 32 Wt % and about 38 Wt % filler, or about 34 Wt %and about 36 Wt % filler. In another embodiment, the formulationcontains between about 25 Wt % and about 35 Wt % filler. Particularly,the formulation contains between about 27 Wt % and about 33 Wt % filler,or about 29 Wt % and about 31 Wt % filler. In another embodiment, theformulation contains between about 20 Wt % and about 30 Wt % filler.Particularly, the formulation contains between about 22 Wt % and about28 Wt % filler, or about 24 Wt % and about 26 Wt % filler. In anotherembodiment, the formulation contains between about 10 Wt % and about 20Wt % filler. Particularly, the formulation contains between about 12 Wt% and about 18 Wt % filler, or about 14 Wt % and about 16 Wt % filler.In another embodiment, the formulation of the present disclosureexcludes a filler.

In one embodiment, the formulation includes a disintegrant. Adisintegrant promotes disintegration of the pill, and dissolution of theactive substance, after administration and upon contact with water. Thedisintegrant may be selected from sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, sodium bicarbonate/citric acid, alginic acid orcombinations thereof. The formulation, or final dosage form, may containbetween about 1.0 Wt % and about 20 Wt % of disintegrant. Particularly,the formulation contains between about 1.0 Wt % and about 10 Wt %disintegrant. In another embodiment, the formulation of the presentdisclosure excludes a disintegrant.

In another embodiment, the formulation includes a dye. A dye is usefulto distinguish or identify the pill of the present disclosure from otherdrug products. The dye may be selected from known dyes suitable for usein pharmaceutical formulations or approved by the FDA for such use. Forexample, the dye may be FD&C Blue No. 2 or a 50/50 Wt % blend of FD&CBlue No. 2 in polyethylene glycol. In one embodiment, the dye andpolyethylene glycol blend cannot be substantially filtered and/orseparated from a resulting solution of water and/or alcohol. Theformulation, or final dosage form, may contain between about 0.10 Wt %and about 15 Wt % dye. Particularly, the formulation may contain betweenabout 0.20 Wt % and about 12.5 Wt % dye, or about 0.50 Wt % and about 10Wt % dye. In some embodiments, the formulation contains at least 0.1%,0.2%, 0.3%, 0.5%, 0.8%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%,5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10%, 11%,12%, 13%, 14%, 15%, and 20% dye. These values can also be used to definea range of dye present in the formulations, e.g., about 3.0% to about5.0%. In another embodiment, the formulation of the present disclosureexcludes a dye.

In another embodiment, the formulation includes a preservative orantioxidant. The preservative or antioxidant reduces or limits thedegradation or deterioration of the abuse deterrent dosage form. Forexample, the components of the oral drug delivery system (e.g., activesubstances, matrix agents) may undergo degradation (e.g., oxidativereduction, chain cleavage) due to oxidation. Preventing degradation isessential to maintaining a proper release profile. For instance, themolecular weight of polyethylene oxide in the formulation affects therelease profile of the active substance. The addition of a preservativeor antioxidant in the formulation that reduces or eliminates thedegradation of the molecular weight of polyethylene oxide is useful tomaintain the release profile of the active substance.

The preservative or antioxidant may be selected from preservatives orantioxidants known to one skilled in the art for use in pharmaceuticalformulations, such as citric acid, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),erythorbic acid, hypophosphorous acid, lactobionic acid,monothioglycerol, potassium metabisulfite, propyl gallate,racemethionine, sodium bisulfite, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium sulfite, sodium thiosulfate, stannouschloride, sulfur dioxide and tocopherols. The formulation, or finaldosage form, may contain between about 0.1 Wt % and about 2.0 Wt %, orabout 0.25 Wt % and about 0.75 Wt % of preservative or antioxidant. Inanother embodiment, the formulation of the present disclosure excludes apreservative or antioxidant.

In some embodiments, the dosage form includes one or more agents thatdecrease the purity of the active substance in an alcohol solution orextraction product. The alcohol purity decreasing agent can reduce orlimit the potential for abuse by decreasing the total weight percent ofactive substance found in the alcohol solution or alcohol basedextraction by increasing the amount of other substances also found inthe solution or extraction. For example, a common form of abuse involvesextraction of active substance using ethanol, or ethanol solutions(e.g., 1%-99% ethanol), resulting in a very pure powder. When introducedto an alcohol solution, components of the oral drug delivery systemcontaining an alcohol purity decreasing agent (e.g., active substances,excipients) may become dissolved in the solution, creating a homogenousliquid which prevents extraction and subsequent alcohol evaporation to avery pure active substance. In one embodiment, the alcohol puritydecreasing agent substantially decreases the purity of a resultingalcohol and/or water solution or powder. In another embodiment, thealcohol purity decreasing agent is not soluble in water. The dosage formmay contain between about 0.1 wt % to 40 wt % alcohol purity decreasingagent. In some embodiments, the formulation contains at least 0.1%,0.25%, 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40% alcohol purity decreasing agent. These values can also be usedto define a range of agent present in the formulations, e.g., about 5.0%to about 15.0%. In another embodiment, the dosage form of the presentdisclosure excludes an alcohol purity decreasing agent.

The alcohol purity decreasing agent may be selected from excipientsknown to one skilled in the art for use in pharmaceutical formulations,such as alginic acid, calcium acetate, carbomers,carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose,hydroxypropyl cellulose, methylcellulose, poloxamers, polyvinyl alcohol,polyvinyl acetate, polyvinylpyrrolidone, and sodium alginate. In aspecific embodiment, the agent is calcium acetate.

In some embodiments, the alcohol purity decreasing agent reducing thepurity of a resulting alcohol and/or water solution or powder by atleast 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or 95%. These values can also beused to define a range of purity reduction, e.g., about 10% to about30%.

The formulation may additionally include at least one additiveindependently selected from surfactants, bulking agents, lubricants,flavorings or combination thereof.

The abuse deterrent pill of the present disclosure is capable ofimmediate release of the active substance. The dosage form may bemanufactured to provide a composition exhibiting an immediate releaseprofile of at least one active substance. As used herein, “immediaterelease” refers to a dosage form that releases the active substance or apharmaceutically acceptable salt thereof, substantially completely intothe gastrointestinal tract of the user within a period of less than anhour, and often less than about 45 minutes from ingestion. In oneembodiment, the amount of active substance released from the dosageform, e.g. oxycodone HCl, by exposure to a deairated water within 45minutes is greater than or equal to 75%. In another embodiment, theamount of active substance released from the dosage form, e.g.hydrocodone bitartrate/acetaminophen, by exposure to a 0.1 Nhydrochloric acid solution within 30 minutes is great than or equal to90%.

In one embodiment, the formulation of the present disclosure releasesgreater than or equal to about 75% of the active substance within 45minutes after administration or via dissolution testing. Particularly,the formulation releases greater than or equal to about 80%, about 85%,about 90%, or about 95% of the active substance within 45 minutes afteradministration or via dissolution testing.

In other embodiments, the formulation of the present disclosure releasesgreater than or equal to about 90% of the active substance within 30minutes after administration or via dissolution testing. Particularly,the formulation releases greater than or equal to about 92%, about 94%,about 96%, or about 98% of the active substance within 30 minutes afteradministration or via dissolution testing.

The formulation of the present disclosure is abuse deterrent and doesnot rapidly release the active substance within a relatively short timeafter administration or dissolution testing begins. In some embodiments,the formulation of the present disclosure releases less than about 95%of the active substance within 20 minutes after administration or viadissolution testing. Particularly, the formulation releases less thanabout 90% of the active substance, less than about 85%, less than about80%, less than about 75%, less than about 70%, less than about 65%, orless than about 60% within 20 minutes after administration or viadissolution testing.

In other embodiments, the formulation of the present disclosure releasesless than about 95% of the active substance within 15 minutes afteradministration or via dissolution testing. Particularly, the formulationreleases less than about 90% of the active substance, less than about85%, less than about 80%, less than about 75%, less than about 70%, lessthan about 65%, or less than about 60% within 15 minutes afteradministration or via dissolution testing.

In one embodiment, the present disclosure relates to an oral, immediaterelease, abuse deterrent dosage form comprising an active substancesusceptible to abuse, wherein less than about 95% of the activesubstance is released from the dosage form within 20 minutes followingadministration, and wherein greater than or equal to 75% of the activesubstance is released from the dosage form within 45 minutes followingadministration. In another embodiment, the present disclosure relates toan oral, immediate release, abuse deterrent dosage form comprising anactive substance susceptible to abuse, wherein less than about 95% ofthe active substance is released from the dosage form within 15 minutesfollowing administration, and wherein greater than or equal to 90% ofthe active substance is released from the dosage form within 30 minutesfollowing administration.

The formulation, or abuse deterrent pill, may also include at least onephysical barrier to reduce abuse. The physical barrier may be theinability of the pill to be abused by pulverizing and swallowing,pulverizing and snorting, pulverizing and injecting, or combinationsthereof. For example, the abuse deterrent pill of the present disclosuremay be incapable of being significantly pulverizing by physical ormechanical force.

One of the most common means of abuse of an orally administered opioidanalgesic involves the manipulation of the oral dosage form in order tocause rapid delivery to the bloodstream via nasal insufflation. In orderfor insufflation to be used as an effective means of abuse, the originaldosage form must be manipulated so as to decrease the particle size ofthe ingested drug to about 0.5 mm or less. A particle size of about 0.5mm or less is necessary for effective intranasal absorption to occur. Bylimiting the quantity of particles under about 0.5 mm that an abuser canobtain by reasonable methods, one can render insufflation ineffective asa means of abuse. One way this physical barrier may be created is bycapturing the active substance susceptible to abuse in a plastic matrixwhich is resistant to being physically broken down to produce particlessmaller than about 0.5 mm.

The dosage form of the present disclosure can inhibit manipulation bygrinding or pulverizing using common equipment, such as a coffeegrinder. For example, the formulation deters abuse by limiting theparticle size to which the formulation may be ground. The formulationprevents the pill, or at least substantial portions of the pill, frombeing ground in particles having a particle size of about 0.5 mm or lessthat may pass through the membrane of the nasal cavity. The dosage formcan also significantly limit the extraction of the active substance bycommon solvents (e.g., cold water or distilled aqueous ethanol) from theformulation. For example, the formulation deters abuse by limiting theability of persons to extract the active substance from the formulation(either intentionally or unintentionally), such that the activesubstance cannot easily be concentrated for parenteral administration.The abuse deterrent formulation may also include, but does not require,the incorporation of other deterrents such as antagonists or irritants.

In one embodiment, the abuse deterrent pill of the present disclosuremay be incapable of being crushed by grinding into a form that may beabused. In a coffee grinder assay as described in Example 1 (e.g.,grinding in a coffee grinder at about 20,000+ rpm and for about 30-60seconds) the pill remains in a form that may not be abused. The coffeegrinder assay may be performed using a commercial coffee grinder, orequivalent, capable of grinding abuse deterrent pills. The pills testedusing the coffee grinder assay have a substantial portion of theresulting particles with a particle size which is not able to be abused,i.e. intranasal administered. Abuse deterrent pills having a substantialamount of such particles reduce the incentive or cost-effectiveness ofpersons to abuse the formulations. For example, a potential abuser whocan only access for intranasal administration less than about 50% of theactive substance will be deterred from abusing the formulation.

Upon exposure to a grinding force (e.g., the coffee grinder assay orequivalent), the abuse deterrent pill may be grinded into particleswherein at least about 50 Wt % of the grinded particles have a particlesize greater than about 0.5 mm. Particularly, upon exposure to agrinding force, the abuse deterrent pill may be grinded into particleswherein at least about 55 Wt % of the grinded particles, 60 Wt % of thegrinded particles, 65 Wt % of the grinded particles, 70 Wt % of thegrinded particles, 75 Wt % of the grinded particles, 80 Wt % of thegrinded particles, 85 Wt % of the grinded particles, 90 Wt % of thegrinded particles, or 95 Wt % of the grinded particles have a particlesize greater than about 0.5 mm.

In another embodiment, the abuse deterrent pill of the presentdisclosure may be capable of forming a hydrogel upon exposure to anaqueous or semi-aqueous solution. The formation of the hydrogel detersabuse by limiting the ability of persons to extract the active substancefrom the formulation, such that the active substance cannot easily beconcentrated for parenteral administration.

In some embodiments, the abuse deterrent pill of the present disclosureis capable of releasing its dye upon introduction to an aqueous orsemi-aqueous solution. The dye provides a visual deterrent to abuse viaparenteral administration by giving the solution a turbid and/or deepcolor. In some embodiments, the dye is not capable of being separatedfrom the solution via nylon, PTFE, coffee or other readily availablefilters or filtering techniques.

In another embodiment, the present disclosure relates to a process forthe production of an oral, immediate release, abuse deterrent pillcontaining at least one active substance susceptible to abuse comprisingprocessing a uniform blend of the at least one active substancesusceptible to abuse, a matrix agent and a plasticizer by hot meltextrusion to produce an extrudate. The extrudate may therein be formedusing a forming unit into the pill.

Hot melt extrusion is a processing technique used to make theformulations and compositions of the present disclosure because itallows for the creation of homogeneous polymer matrices with specificabuse deterrent properties. For example, by varying the formulation andthe processing parameters specific properties such as dissolution time,pulverization resistance, material processability, and stability can beselectively modified. Formulations that include polymer matrix agents(e.g., polyethylene oxide) can provide a unique advantage as they allowfor formulations in which release characteristics can be controlledwhile also creating a physical barrier that prevents abuse (e.g.,through means of nasal inhalation or intravenous injection).Furthermore, in a hot melt extrusion process, process analytic data canbe provided in real time. The process may also be adapted for continuousprocess manufacturing procedure as opposed to traditional batch to batchprocessing.

The abuse deterrent pill of the present disclosure may be formed by hotmelt extrusion using commercially available extruders, such as a twinscrew extruder. Several factors of the extrusion process may affect thefinal extrudate including: screw design (sheer rating), screw speed,temperature profile, feed rate, dwell time, die pressure and die size.These factors may be varied to obtain an extrudate with desiredprocessing capabilities such that the extrudate is uniform, holds itsshape, and is capable of being formed into pills by a forming unit.

An exemplary extruder and forming unit system (10) is shown in FIG. 1.The extruder (14) includes a hopper or feeding unit (12) wherein auniform blend of the formulation is made or transferred to. The uniformblend is fed into the inlet (16) of the extruder (14) by starve feedingvia a gravimetric or volumetric dosing unit. The formulation of thepresent disclosure is preferably uniformly blended prior to introductionto the extrusion process. Insufficient blending of the components mayproduce a non-uniform extrudate and non-uniform abuse deterrent pillshaving inconsistent amounts of active substance. Over-blending mayproduce a poorly performing formulation. The blending process may bemonitored using a process analytical technique to determine when auniform blend is achieved. In one embodiment, the mixing bin or hopper(12) may be equipped with a near-infrared (NIR) monitoring system forin-line, continuous monitoring of the blend.

In one embodiment, monitoring of the blending process by NIR involvespreparing a NIR standard spectrum for each formulation. The NIR standardspectra may be prepared empirically by monitoring the blending ofdifferent batches of the formulation. The blending conditions and/orextrusion process may be correlated with NIR spectra to determine a NIRstandard spectrum for a given dosage form. Once the optimum NIRmonitoring spectrum and conditions are determined, the formulation isblended until the NIR standard is achieved. One of ordinary skill in theart armed with the present disclosure can implement a near-infraredmonitoring system for in-line, continuous monitoring of the blend.

The extruder (14) then processes the blend into a melt and passes theextrudate (50) out of the extruder (14) through a die section (30) andthrough a die outlet (18). The extruder (14) may have temperature zones(20-30) and pressure zone (40-43). These zones may include components toheat and pressurize the extruder (14) or may include sensors to measurethe temperature and/or pressure of each particular zone.

As used herein the term melt temperature refers to the temperature atwhich an excipient changes from solid to liquid state. As used hereinthe term softening temperature refers to the temperature at which anexcipient changes from solid form into a malleable, dynamic solid.

The temperature profile of the extruder (14) is important to obtain auniform extrudate (50) with little to no degradation products. Heat maybe applied to soften, and in some embodiments to melt, the excipients(e.g., matrix agent, plasticizer) to form a homogenous matrix toencapsulate the active substance. The extruder temperature profile, orthe temperatures in the extruder zones (20-30), is preferably kept belowthe melting point, and often the degradation point, of the activesubstance.

For example, the melting temperature of polyethylene oxide is about 67°C. and of polyethylene glycol is about 63° C. Common active substancesbegin to melt at temperatures much higher than this. For example, themelt temperature of oxycodone HCl is about 219° C. and of hydrocodonebitartrate is about 147° C. Preferably, the temperature of one or moreof the zones (20-30) is kept at or below the melting point of the activepharmaceutical ingredients. In particular, the temperature of one ormore of the zones (20-30) is kept below about 120° C., 110° C., 100° C.,90° C., 80° C., 75° C., 70° C., 65° C., or 60° C.

In one embodiment, the temperature of at least one of the extruder zones(20-30) is kept at or below the melting point of the activepharmaceutical ingredients. Particularly, the temperature of at leastone of the zones is kept below about 120° C., about 110° C., about 100°C., about 90° C., about 80° C., about 75° C., about 70° C., about 65°C., or about 60° C.

In another embodiment, the temperature of at least two of the extruderzones (20-30) is kept at or below the melting point of the activepharmaceutical ingredients. Particularly, the temperature of at leasttwo of the zones is kept below about 120° C., about 110° C., about 100°C., about 90° C., about 80° C., about 75° C., about 70° C., about 65°C., or about 60° C.

In another embodiment, the temperature of at least three of the extruderzones (20-30) is kept at or below the melting point of the activepharmaceutical ingredients. Particularly, the temperature of at leastthree of the zones is kept below about 120° C., about 110° C., about100° C., about 90° C., about 80° C., about 75° C., about 70° C., about65° C., or about 60° C.

In another embodiment, the temperature of at least four of the extruderzones (20-30) is kept at or below the melting point of the activepharmaceutical ingredients. Particularly, the temperature of at leastfour of the zones is kept below about 120° C., about 110° C., about 100°C., about 90° C., about 80° C., about 75° C., about 70° C., about 65°C., or about 60° C.

In another embodiment, the temperature of at least five of the extruderzones (20-30) is kept at or below the melting point of the activepharmaceutical ingredients. Particularly, the temperature of at leastfive of the zones is kept below about 120° C., about 110° C., about 100°C., about 90° C., about 80° C., about 75° C., about 70° C., about 65°C., or about 60° C.

In another embodiment, the temperature of at least six of the extruderzones (20-30) is kept at or below the melting point of the activepharmaceutical ingredients. Particularly, the temperature of at leastsix of the zones is kept below about 120° C., about 110° C., about 100°C., about 90° C., about 80° C., about 75° C., about 70° C., about 65°C., or about 60° C.

In another embodiment, the temperature of all of the extruder zones(20-30) is kept at or below the melting point of the activepharmaceutical ingredients, with the optional exception of the die zone.Particularly, the temperature of all of the zones is kept below about120° C., about 110° C., about 100° C., about 90° C., about 80° C., about75° C., about 70° C., about 65° C., or about 60° C., with the optionalexception of the die zone.

The temperature of the die (18, 30) may be maintained at a slightlyhigher temperature than the temperature of one or more of the otherzones. In some embodiments, the die temperature (18, 30) is held at orslightly above the melting point of the extrudate, or the matrix andplasticizer, to ensure a uniform extrudate (50) exiting the die outlet(18).

The extruder (14) also has a pressure profile. Pressure is important tomelt the excipients to make mixing more efficient and to force theextrudate (50) through the die outlet (18) to exit the extruder (14) ina consistent manner. Particularly, the pressures in the zones and alsothe pressure at the die outlet (18), is kept at or above about 5 bar,about 10 bar, about 15 bar, about 20 bar, about 30 bar, about 40 bar,about 50 bar, about 60 bar, about 70 bar, about 80 bar, about 90 bar,about 100 bar or about 110 bar.

In one embodiment, the pressure of one or more of the pressure zones(40-43) in the extruder (14) is kept at a high enough pressure toachieve melting, compression, and mixing of the matrix and plasticizingagents with non-melting excipients (e.g., API, filler, disintegrants,and antioxidant) while the temperature of one or more of the temperaturezones (20-30) is at or slightly below the melting point at standardpressure of these agents. The increased pressure allows for moreefficient mixing due to compaction and shearing forces without having todramatically increase temperature. These lower temperatures reduce, orsubstantially eliminate, the formation of degradation products from theactive substances. In one embodiment, the pressure produced on the die(43) of the extruder (14) is kept sufficiently high enough to reducepulsating flow and ensure a uniform extrudate (50) is delivered thoughthe die outlet (18). A sufficiently high pressure assists in compactingthe homogenous melt into a processable strand of desired diameter.

In one embodiment, the pressure of at least one of the pressure zones(40-43) is kept at a high enough pressure to achieve melting,compression, and mixing of the matrix and plasticizing agents with theactive substance and any non-melting excipients. Particularly, thepressure of at least one of the zones is kept at or above about 5 bar,about 10 bar, about 15 bar, about 20 bar, about 30 bar, about 40 bar,about 50 bar, about 60 bar, about 70 bar, about 80 bar, about 90 bar,about 100 bar or about 110 bar

In another embodiment, the pressure of at least two of the pressurezones (40-43) is kept at a high enough pressure to achieve melting,compression, and mixing of the matrix and plasticizing agents with theactive substance and any non-melting excipients. Particularly, thepressure of at least two of the zones is kept at or above about 5 bar,about 10 bar, about 15 bar, about 20 bar, about 30 bar, about 40 bar,about 50 bar, about 60 bar, about 70 bar, about 80 bar, about 90 bar,about 100 bar or about 110 bar

In another embodiment, the pressure of at least three of the pressurezones (40-43) is kept at a high enough pressure to achieve melting,compression, and mixing of the matrix and plasticizing agents with theactive substance and any non-melting excipients. Particularly, thepressure of at least three of the zones is kept at or above about 5 bar,about 10 bar, about 15 bar, about 20 bar, about 30 bar, about 40 bar,about 50 bar, about 60 bar, about 70 bar, about 80 bar, about 90 bar,about 100 bar or about 110 bar

In another embodiment, the pressure of all of the pressure zones (40-43)is kept at a high enough pressure to achieve melting, compression, andmixing of the matrix and plasticizing agents with the active substanceand any non-melting excipients. Particularly, the pressure of all of thezones is kept at or above about 5 bar, about 10 bar, about 15 bar, about20 bar, about 30 bar, about 40 bar, about 50 bar, about 60 bar, about 70bar, about 80 bar, about 90 bar, about 100 bar or about 110 bar

The melt extrudate may be optionally analyzed within the extruder (14)using near-infrared technology. NIR spectroscopy can be used as anon-invasive alternative to high performance liquid chromatographytechniques. A NIR probe (80) may be included within the extruder (14).The wavelengths and intensities at which raw organic materials of themelt extrudate absorb light energy can be plotted to produce spectra tocompare against a standard. With the spectrum of the API known, it canbe used to determine and monitor the % wt of the active pharmaceuticalingredient present in the extrudate in real time.

The extrudate from an extruder is directly formed into a pill using aforming unit, provided that the size or shape of the extrudate may beadjusted prior to introduction to the forming unit (e.g., via a ropesizer). In some embodiments, the extrudate is directly formed into adosage form without a further processing step, such as a cutting ormilling step. The forming unit may be a unit capable of forming the pillwithout cutting or milling the extrudate. The forming unit may be acalendar, rotary, or a chain forming machine. As shown in FIG. 1, theextrudate (50) may be shaped into the abuse deterrent form (70) by aforming unit (60). In one embodiment, the extrudate (50) is shaped intothe abuse deterrent form (70) by a calendaring process.

The forming unit (60) may comprise two rotating components each havingmolds (62) inset in the rotating components and aligned such that themolds (62) overlap with each other as the rotating components interface.When the extrudate (50) is guided between the rotating components of theforming unit (60), the offset and aligned molds (62) (or cavities)accept the extrudate and form the extrudate into the dosage form asprovided by the shape of the molds (62), provided a sufficient amount ofextrudate is guided between and supplied to the rotating components.

In another embodiment, the forming unit may also comprise of a rotatingset of punch dies with accompanying pinching ring, e.g. a chain dieforming unit. FIG. 2 shows an embodiment of a chain forming unit. Thechain forming unit includes an upper and lower chain system (110 and112) and tooling (100) to form an incoming extrudate (56) into formedpills (19). When the extrudate (56) is fed into the chain die formingunit, the ring tooling (100) pinches the extrudate (56) to the exactweight of the finished pill and simultaneously presses it into a finalform by the punches via a cam track. In one embodiment, the centripetalforces produced by the rotation of the machine aid in the ejection ofthe final pill form (19).

The extruder/forming unit system (10) may also be equipped with anadditional component or transfer unit to assist the transfer of theextrudate (50) from the extruder (14) to the forming unit (60). Thetransfer unit may be capable of controlling the temperature, pressure,environment and/or shape of the extrudate. For example, the transferunit may include heated/cooled sizing rollers which process theextrudate (50) into a consistent size (e.g., diameter) before enteringthe forming unit, cooling air jets, and extrudate diameter monitoring.The transfer unit may also be capable of guiding the extrudate into andbetween the rotating components of the forming unit (60).

For example, the extrudate may be adjusted by an apparatus that re-sizesthe extrudate, re-shapes the extrudate, or both. FIG. 3 shows anembodiment of an extrudate sizing apparatus (e.g., rope sizer). The ropesizer includes a number of consecutive rollers (90-96) to re-size orre-shape an incoming extrudate (52), either from the extruder (14) orfrom another step. The number, shape and orientation of the rollers(90-96) may vary depending on the degree of re-sizing and/or re-shapingdesired. In some embodiments, the extrudate will be re-sized into asmaller diameter extrudate. In these embodiments, the rotating rollerswill rotate at consecutively faster speeds. As such, the re-sized and/orre-shaped extrudate having a smaller diameter will be moving at a fasterspeed exiting the rope sizer.

The size and shape of the extrudate (50) may be designed to efficientlyinteract with different shaped molds (62). For example, an oval shapedextrudate may be formed to interact with a wide and shallow set of molds(62). Also, the speed and mass (or volume) of the extrudate (50) may bedesigned to efficiently interact with the size and speed of the formingunit. The speed and mass (or volume) of the extrudate (50) guidedbetween the rotating components of the forming unit (60) should besufficient to fill each set of molds completely with no voids.

The size and shape, and the speed and mass (or volume) of the extrudate(50) as well as size and shape of the molds (62) and the speed of theforming unit may be matched to reduce the amount of excess extrudatethat is not formed into the dosage form (e.g., reduce waste). The twoprocesses may be synchronized by attaching both to the same drivesystem. Preferably, the forming unit is capable of forming abusedeterrent pills from the extrudate wherein more than about 90% of theextrudate is utilized (e.g., formed into the dosage form). Morepreferably, the forming unit utilizes more than about 95% of theextrudate. Even more preferably, the forming unit utilizes more thanabout 99% of the extrudate.

The molds (62) may optionally be formed with a non-uniform bottom orlower surface to allow for easy removal of the pill after formation. Themolds (62) may also have markings in the bottom or lower surface toprovide marking on the abuse deterrent pills upon formation.

After formation, the quality, volume and weight of each pill may bedetermined using an automated optical inspection technique. The optionalinspection technique combines a weight determination step and a visualinspection step into a single step. For example, the visualization stepmay include taking multiple pictures of each pill. From these pictures,an estimated volume is determined. The estimated volume and thepre-determined density of the composition of the formulation may providean estimated weight for each pill. Those pills that satisfy certainquality, volume and weight criteria will pass the optical inspection.

In another embodiment, the present disclosure relates to an process forthe production of an oral, immediate release, abuse deterrent pillcontaining at least one active substance susceptible to abuse comprisingcombining the at least one active substance susceptible to abuse, amatrix agent, and a plasticizer in a hopper to form a mixture; blendingthe mixture in the hopper until a uniform blend is achieved; monitoringthe mixture during blending using a process analytical technique todetermine when a uniform blend is achieved; feeding the uniform blendinto an extruder; processing the uniform blend by hot melt extrusion toproduce an extrudate; optionally monitoring of the extrudate at the diehead via PAT NIR probe; transferring the extrudate to a forming unitusing a transfer line capable of controlling the temperature, pressure,environment, and/or shape of the extrudate; forming the extrudate usingthe forming unit into the pill; and determining the quality, volume andweight of the pill using an optical inspection technique.

In another embodiment, the present disclosure relates to a method oftreating pain comprising administering to an individual in need thereofa therapeutically effective amount of a dosage form as described herein.The dosage form provides rapid onset of analgesia for the treatment ofmoderate to severe pain.

The disclosures of all cited references including publications, patents,and patent applications are expressly incorporated herein by referencein their entirety. Further, when an amount, concentration, or othervalue or parameter is given as either a range, preferred range, or alist of upper preferable values and lower preferable values, this is tobe understood as specifically disclosing all ranges formed from any pairof any upper range limit or preferred value and any lower range limit orpreferred value, regardless of whether ranges are separately disclosed.Where a range of numerical values is recited herein, unless otherwisestated, the range is intended to include the endpoints thereof, and allintegers and fractions within the range. It is not intended that thescope of the invention be limited to the specific values recited whendefining a range.

The present invention is further defined in the following Examples. Itshould be understood that these Examples, while indicating preferredembodiments of the invention, are given by way of illustration only.

EXAMPLES Example 1

Abuse deterrent formulations were prepared containing acetaminophen.Acetaminophen was utilized as a tracer in place of oxycodone HCl due toits availability, cost, similar particle size, and solubility profile.Tables 1-3 show the exemplary ranges of components for the abusedeterrent formulations.

TABLE 1 Exemplary Abuse Deterrent Formulation Ranges Components Wt %Active Substance  0.1-30.0 Matrix Agent (50 K to 300 K Daltons)10.0-90.0 Plasticizer (1 K to 15 K Daltons)  5.0-60.0 Filler  0.0-40.0Disintegrant  0.0-10.0 Antioxidant(s)  0.0-2.0 Dye  0.0-20.0 AlcoholPurity Decreasing Agent  0.0-30.0

TABLE 2 Exemplary Abuse Deterrent Formulation Ranges Components Wt %Active Substance  0.1-15.0 Polyethylene Oxide (50 K to 300 K Daltons)10.0-90.0 Polyethylene Glycol (1 K to 15 K Daltons)  5.0-60.0Microcrystalline Cellulose 20.0-40.0 Crospovidone (Disintegrant) 0.0-10.0 Citric Acid (Antioxidant 1)  0.0-1.0 Butylated hydroxytoluene(Antioxidant 2)  0.0-1.0 Calcium Acetate  0.0-10.0

TABLE 3 Exemplary Abuse Deterrent Formulation Ranges Components Wt %Active Substance  5.0-10.0 Polyethylene Oxide (50 K to 300 K Daltons)30.0-50.0 Polyethylene Glycol (1 K to 15 K Daltons) 15.0-30.0 LactoseMonohydrate  5.0-15.0 Disintegrant  2.5-7.5 Antioxidants  0.5-1.5 Dye 0.5-1.5 Alcohol Purity Decreasing Agent  0.0-30.0

Immediate release abuse deterrent pills containing acetaminophen weremanufactured according to the formulation provided in Table 1.

The formulation was blended prior to extrusion. Extrusion was performedby means of a twin screw extruder of type Coperion ZSK26. To achieve auniform extrudate with good processing capabilities a medium sheer screwdesign was used at a relatively slow screw speed (120 RPM). Thetemperature profile was designed to immediately melt the matrix andplasticizer agents (e.g., the polyethylene oxide and polyethyleneglycol). Thereafter, the temperature was adjusted to be at or slightlybelow the melting temperature of the extrudate at standard pressure toachieve mixing. Adequate mixing was achieved by maintaining highpressures in the extruder.

At times, the die was heated to a temperature above the general meltingtemperature of the extrudate. It was found that at die temperatures atthe melting temperature of the extrudate, the portion of the extrudatein contact with the inside die surface sheared off due to friction. Anincrease in die temperature allowed the outside surface of the extrudateto melt and slide along the die producing a uniform extrudate. Operatingtemperatures and pressures are provided in Table 5. The temperature andpressure zones in Table 5 correspond to the zones shown in FIG. 1.

TABLE 4 Extrusion Temperature and Pressure Temp Pressure Zone 1 63-67°C. Zone 2 58-62° C. Zone 3 58-62° C. Zone 4 57-61° C. Zone 5 57-61° C.Zone 6 57-61° C. Zone 7 57-61° C. Zone 8 57-61° C. Zone 9 57-61° C. Zone10 57-61° C. Die 67-71° C. Melt Pressure 20-100 bar

The temperature profile, feed rate, and die size all have an effect onthe pressure produced on the die head. A die size of 3-5 mm was used.The temperature profile was kept relatively static. The feed rate wasadjusted to maintain a consistent and high pressure on the die head ofabout 50 bar. A pressure maintained at the die head of about 50 bar ormore produced uniform extrudates.

A Carver Press was then used to form the extrudate into pills. A CarverPress is a manual hand press which utilizes a free standing set ofNatoli upper and lower punches that meet at the die. Dedicated toolingwas made for the experiment in order to produce an embossed, 100 mgpill.

The extrudate was hand cut, based on weight (100 mg). The die was placedon top of the bottom punch, the cut extrudate was placed in the diecavity, and the top punch placed through the top section of the die. Thecut extrudate was formed into a pill at no more than 1 metric ton offorce using the Carver Press and Natoli die set.

Dissolution Testing

The abuse deterrent pills prepared were tested for dissolution.Dissolution testing was performed with reference to USP Monograph onOxycodone HCl Tablets. These tests were performed on a dissolutionapparatus utilizing UPS <711> Apparatus II (Paddles), with 500 mLde-aerated water as media and a paddle speed of 50 rpm. Japanese SinkerBaskets (Part Number PSCUSBSK-JPMAG) were utilized. A 1 mL sample waspulled at 20 and 45 minutes and submitted for HPLC analysis. HPLCconditions were taken from the USP Monograph in order to observe therelease of acetaminophen. The HPLC conditions are as follows: InjectionVolume: 20 μL; Flow Rate 1.5 mL/min; Detection: UV at 295 nm; ColumnTemp: 25° C.; Autosampler Temperature: ambient; Gradient: Isocratic; andRuntime: 5 minutes. The specification for this dissolution testing wasNLT 75% (Q=70%) at 45 minutes.

The weight percent of matrix agent (e.g., polyethylene oxide) in theformulation has a direct correlation with both the release profile andADF properties. The effect of varying the weight percent of the matrixagent (e.g., polyethylene oxide) in the formulation on the releaseproperties and ADF was tested. Two different molecular weightpolyethylene oxides were used, namely 300K Daltons and 600K Daltons. Thegeneral formulation was tested for dissolution using the two differentpolyethylene oxides (i.e., 300K Daltons and 600K Daltons). For theseexperiments, polyethylene glycol was used to offset the differing weightpercentages of PEO.

FIG. 4 shows the percent release of the active substance (i.e.,acetaminophen dissolution in 45 minutes) versus the weight percent ofthe matrix agent (e.g., polyethylene oxide or PEO) for two similar abusedeterrent pill formulations having different molecular weight matrixagents (e.g., 300K Daltons PEO vs. 600K Daltons PEO). Based on FIG. 4,the more polyethylene oxide present in the formulation the lower thepercent release of active after 45 minutes.

Abuse Deterrent Testing—Coffee Grinder Assay

The abuse deterrent pills were also tested for resistance topulverizing/grinding using a coffee grinder assay. The testedformulations contained only 300K Dalton polyethylene oxide. The Wt % ofthe polyethylene oxide was varied. Polyethylene glycol was again used tooffset the differing weight percentages of PEO. Three (3) pills for eachspecific Wt % of polyethylene oxide were selected and placed in acommercially available coffee grinder (Mr. Coffee®, model number IDS55).The coffee grinder was run for 30 seconds with occasional pulsing. Thegrinded pills were tested for particle size analysis using a sonicsifter (screen size 35 Mesh) for 2 minutes. The 35 Mesh corresponds to asieve size of 0.5 mm. The amount of particles below 0.5 mm for eachformulation is shown in FIG. 5. FIG. 5 shows that with increasing weightpercent of polyethylene oxide the ADF properties are enhanced. Thepercent of particles smaller than 0.5 mm decreases with increasingweight percent of polyethylene oxide. These results show that byincreasing the content of polyethylene oxide the percentage of particlessmall enough to be abused through means of insufflation is decreased.

Example 2

Immediate release abuse deterrent pills containing acetaminophen oroxycodone HCl were manufactured according to the formulation provided inTable 1.

A 150 g batch of each formulation was processed and formed into abusedeterrent pill by the process described in Example 1. Exemplary extruderoperating temperatures and pressures are provided in Table 29.

TABLE 5 Extrusion Temperature and Pressure Temp Pressure Zone 1 63-67°C. Zone 2 57-61° C. Zone 3 57-61° C. Zone 4 58-62° C. Zone 5 58-62° C.Zone 6 58-62° C. Zone 7 58-62° C. Zone 8 58-62° C. Zone 9 58-62° C. Zone10 58-62° C. Die 68-72° C. Actual Melt Pressure 20-100 bar

All of the abuse deterrent pills were tested for dissolution and abusedeterrence using the tests described in Example 1. All abuse deterrentpills exhibited a greater than 80% of particles having a particle sizegreater than 0.5 mm in the coffee grinder assay. All abuse deterrentpills also exhibited a more than 75% release within 45 minutes duringdissolution testing.

In particular, abuse deterrent pills containing oxycodone HCl weretested for dissolution according to the test described in Example 1. Thedissolution results, listed as percent label claim of oxycodone, areshown in Table 6.

TABLE 6 Dissolution Data Sample % Label Claim Abuse Deterrent Pill, TestFormulation 1 20 Minutes (average of 3 pills) 54.9 45 Minutes (averageof 3 pills) 81.3 Abuse Deterrent Pill, Test Formulation 2 20 Minutes(average of 3 pills) 57.8 45 Minutes (average of 3 pills) 87.9

As shown in Table 6, the release profiles are comparable and both areconsistent with immediate release formulations.

The abuse deterrent pills were put on accelerated stability under 40°C./75% RH conditions for 1 and 2 Months. Dissolution testing wasrepeated. The results are shown in the Table 7.

TABLE 7 Dissolution Data on Stability % Label Claim % Label Claim Sample(1 Mo) (2 Mo) Abuse Deterrent Pill, Test Formulation 1 20 Minutes(average of 6 pills) 56.39 54.24 45 Minutes (average of 6 pills) 85.1881.63 Abuse Deterrent Pill, Test Formulation 2 20 Minutes (average of 6pills) 44.80 51.12 45 Minutes (average of 6 pills) 75.75 80.24

As shown in Table 7, the release profile and the percent label claim forthe abuse deterrent pills on stability are comparable to each other andto the original pills. The release profile for the abuse deterrent pillsis consistent with immediate release formulations. The abuse deterrentpills exhibited excellent stability under accelerated conditions.

Abuse Deterrent Testing—Coffee Grinder Assay

The abuse deterrent pills containing oxycodone HCl were tested forresistance to pulverizing/grinding using the coffee grinder assaydescribed in Example 1. Three (3) pills were selected and placed in thecoffee grinder. The coffee grinder was run for 30 seconds withoccasional pulsing. The grinded pills were tested for particle sizeanalysis using a sonic sifter (screen size 35 Mesh). The results areshown in Table 8.

TABLE 8 Pulverizing/Grinding Test (30 seconds) Gross Wt (mg) Tare Wt(mg) Net Wt (mg) % 35 Mesh 40461.70 40208.03 253.67 84 Pan 160822.45160822.45 49.54 16 Total 303.21 100

The tested was repeated with the coffee grinder run for a longer period(2 minutes). The grinded pills were tested for particle size analysisusing a sonic sifter (screen size 35 Mesh). The results are shown inTable 9.

TABLE 9 Pulverizing/Grinding Test (2 minutes) Gross Wt (mg) Tare Wt (mg)Net Wt (mg) % 35 Mesh 40411.21 40209.15 202.06 73 Pan 160913.98160839.25 74.73 27 Total 276.79 100

As shown in Tables 8 and 9, a majority of the grinded pills (84% and73%) have a particle size larger than 0.5 mm. These pills are abusedeterrent compliant.

Additional abuse deterrent pills containing oxycodone HCl or hydrocodonebitartrate were tested for resistance to pulverizing/grinding using thecoffee grinder test described above. The results are shown in Table 10.A majority of the grinded pills (89%+) has a particle size larger than0.5 mm. These pills are abuse deterrent compliant.

TABLE 10 Pulverizing/Grinding Test (2 minutes) % particles > % particles< 500 microns 500 microns Test Formulation 3 89 11 (oxycodone HCl) TestFormulation 4 89 11 (hydrocodone bitartrate)

The abuse deterrent pills were also tested for hardness. Hardnesstesting was performed using a Sotax HT1 hardness testing machine. Twodifferent formulations were tested for hardness, one containingacetaminophen and one containing oxycodone HCl.

For each formulation, three (3) formed pills were tested for hardness.All the hardness tested pills exhibited a hardness of >999N.

Example 3

In order to attain the release profile required by USP standards forimmediate release, the use of a disintegrant was tested. Severaldisintegrants were evaluated including croscarmellose sodium, sodiumstarch glycolate, cross-linked polyvinylpyrrolidone, sodiumbicarbonate/citric acid and alginic acid. These disintegrants workthough several methods such as swelling, wicking, and deformation in anaqueous environment to break up a formulation and thus increase surfacearea to aid in rapid API release.

Experiments utilizing polyethylene oxide 300K Daltons showed nosignificant improvement in dissolution rates with increased weightpercent of croscarmellose sodium (CCS). CCS is water soluble and canform a gel at increasing percentages which may prevent disintegration.Sodium starch glycolate (SSG) was tested and found to rapid swell withminimal gelling effects. SSG was tested alone as well as with 5 Wt % and10 Wt % sodium bicarbonate/citric acid acting as an effervescent. Allcombinations produced passing dissolution at 45 minutes. Additionalexperiments utilizing alginic acid produced similar passing dissolutionresults at 45 minutes.

Cross-linked polyvinylpyrrolidone was also tested. Cross-linkedpolyvinylpyrrolidone was tested alone as well as with 5 Wt % and 10 Wt %sodium bicarbonate/citric acid. Cross-linked polyvinylpyrrolidone alsoproduced passing dissolution results. Cross-linked polyvinylpyrrolidoneis highly hydrophilic and water insoluble. It acts through a wicking andswelling mechanism. Due to it being water insoluble, it does not form agel in any concentration. Cross-linked polyvinylpyrrolidone providedbetter dissolution results regardless of Wt % sodium bicarbonate/citricacid which is believed to be due to its insoluble, non-gel formingnature. Thus, cross-linked polyvinylpyrrolidone was determined to be apreferred disintegrant for this formulation.

Extraction Example

The inclusion of one or more dyes in a drug formulation is one method torender a formulation abuse deterrent. Significant discoloration of anextraction product from a formulation subject to abuse can discourage apotential abuser from using (e.g., injecting or ingesting) theextraction product. A study was conducted to investigate the effect ofdyes in the formulations of the present disclosure. Extraction productsfrom whole or cut formulations were visually inspected to determineabuse deterrence following alcohol extraction, and also followingsubsequent filtration.

The purpose of this study is to perform and summarize the results of analcohol extraction, filtration, and visual examination of the resultingextraction solution for different formulations. Formulations of CIInarcotic drug products can be modified from their intended dosage formin order to receive immediate release of the full dose of the activepharmaceutical ingredient into the body. This is known as making thedrug product “abusable.” Formulation development has occurred which isintended to reduce the ability of patients to modify the products intothis “abusable” form. Extrusion and compress-and-curing are two methodsfor manufacturing CII drug products. Both methods, when formulatedappropriately, possess characteristics which reduce the ability ofpatients to modify the products into an “abusable” form (when comparedto traditional methods).

Twin Screw extrusion can be described as mixing a blended formulation byusing shear forces. The co-rotating screws create shear/frictionalforces through material contact between the two screws and between thescrews and barrel wall. The shear forces work on the material based onits viscosity (inter-particulate friction) to create a homogenouspolymer melt. The heated barrels control the melt by maintainingconstant temperatures in the various zones of the extruder as well asadd additional heat to maintain energy in the process. This happens in asimultaneous continuous process while the material is transferredthrough the extruder. The polymer melt can then be pushed through a dieto form a uniform extrudate. This differs from compress-and-curing whichcan be described as initially compressing (with force) the blendedformulation and then curing (with heat) after the compression in aseparate sequential process to produce a finished drug product. CII drugproducts which utilize each manufacturing method are currentlycommercially available. In some embodiments, the formulation of thepresent disclosure is formed by an extrusion process under sufficientshear stresses to impart strength and stability to the formulation. Theformulation can be prepared using an extruder wherein shear forces,pressure, and heating are be applied together or separately in differentzones of the extruder. In some embodiments, the formulation is preparedby reaching a melt flow temperature of the specific formulation in theextruder to assist in producing a uniform extrudate (i.e., localizeduniformity). Compress-and-curing formulations are not similarlyprepared.

Three principal methods of modifying CII drug products in order to makethem “abusable” exist, namely cutting, grinding, and extraction. Cuttingthe dosage form can be performed in order to increase the surface areaof the product prior to ingesting it in an effort to increase the rateof dissolution into the digestive tract. Cutting can also be used toincrease the efficiency of extraction by breaking/removing the aqueous,non-ethanol soluble coating applied to many commercially availabledrugs. Cutting alone, however, is not sufficient to render a formulationabuseable. Readily available tools used for cutting are razor blades andcommon kitchen scissors. Grinding the dosage form is performed in orderto decrease the particle size of the product in an effort to insufflate(snort) for immediate release into the blood vessels of the nasalpassages. Additional abuse pathways exist which follow the grinding ofthe product. A readily available tool used for grinding is acommercially available coffee grinder. Extraction is performed in orderto dissolve the active pharmaceutical ingredient of the dosage form intoa liquid which can be filtered and subsequently swallowed, injected, orotherwise abused. A readily available tool used for extraction is highpotency alcohol (i.e., ≥190 proof (95%)).

Color is one identifying characteristic of commercial drug products.Color can be applied to the dosage form in two ways: dye or coating.High potency alcohol (i.e., ≥190 proof (95%)) is one extraction solventthat can be used by abusers for APIs which are insoluble in water or inorder to separate the API from other water soluble excipients. Dyes orcoatings can potentially be used to alter the physical appearance of theextracted solution of drug product (i.e., turn the resulting solution anoticeable color).

In this study, 190 proof ethanol was utilized as an extraction solvent.A commercially available coffee filter was used to filter out anyparticulate matter of several drug products. The resulting solution wasanalyzed for physical appearance. The difference in physical appearance(if any) between drug products which are dyed or coated was evaluated.

Additionally, a non ADF drug product which utilizes traditionalcompression manufacturing methods (Roxicodone® 15 mg, manufactured byMallinckrodt, Inc.) was evaluated for comparison purposes.

Experimental: The samples tested include ADF Oxycodone 5 mg and 30 mg(Immediate Release) and ADF Oxycodone 10 mg and 80 mg (Extended Release)as described in the present disclosure, as well as Roxicodone® 15 mg(Mallinckrodt, Inc.), Opana® ER 5 mg (reformulated) (Endo HealthSolutions); Opana® ER 40 mg (reformulated) (Endo Health Solutions);Oxycontin® 10 mg (reformulated) (Purdue Pharma); Oxycontin® 40 mg(reformulated) (Purdue Pharma); Oxycontin® 60 mg (reformulated) (PurduePharma); Oxycontin® 80 mg (reformulated) (Purdue Pharma). A summary ofall of the samples tested is provided in the table below.

TABLE 11 List of Samples Tested Dosage Units Descriptions Manufac.Manufac. Process Release Sample Sample Name Process Color API Timeframe1 Roxicodone ® 15 mg Compression Dye Oxycodone Immediate 2  IR 5 mgExtrusion Dye Oxycodone Immediate 3 IR 30 mg Extrusion Dye OxycodoneImmediate 4 ER 10 mg Extrusion Dye Oxycodone Extended 5 ER 80 mgExtrusion Dye Oxycodone Extended 6  Opana ® ER 5 mg Extrusion CoatingOxymorphone Extended 7 Opana ® ER 40 mg Extrusion Coating OxymorphoneExtended 8 Oxycontin ® 10 mg Compress & Cure Coating OxycodoneControlled 9 Oxycontin ® 40 mg Compress & Cure Coating OxycodoneControlled 10 Oxycontin ® 60 mg Compress & Cure Coating OxycodoneControlled 11 Oxycontin ® 80 mg Compress & Cure Coating OxycodoneControlled

The formulations of the samples of the present disclosure tested, i.e.,samples 2-5, are provided in the table below.

TABLE 12 Formulations of Samples Tested Sample Sample Sample SampleComponent 2 3 4 5 Oxycodone HCl  5.00% 30.00%  5.00% 33.33% PEO, 100KDaltons 35.00% 35.00% 40.00% 40.00% Microcrystalline Cellulose PH 10122.25% 12.25% Lactose Monohydrate 316 21.00% 11.65% Hypromellose, K100M37.50% 20.00% PEG, 8K Daltons 15.00% 10.00% 15.75%  4.67% Citric Acid 1.00%  1.00%  1.00%  1.00% Dye  0.75%  0.10%  0.75%  1.00% Total weight100 mg 100 mg 200 mg 240 mg Release characteristics IR IR ER ER

In additional embodiments of the present disclosure, the amount ofactive substance in the formulation can range from about 0.50 Wt % toabout 40 Wt %. Particularly, the amount of active substance in theformulation may range from about 1.0 Wt % to about 35 Wt %, or fromabout 5.0 Wt % to about 33 Wt %. In additional embodiments of thepresent disclosure, the amount of plasticizer (e.g., PEG) can range fromabout 0.25 Wt % and about 20 Wt % plasticizer.

For each sample, both whole and cut dosage units were tested. For wholedosage units, two (2) whole dosage units were placed in a 25 mLErlenmeyer flask containing 10 mL of EtOH. For cut dosage units, all cutpieces of the dosage unit were placed in similar flasks. Cut dosageunits were cut into about 8 pieces using diagonal pliers. Each flask wassealed with parafilm and shaken on a platform shaker for at least 10hours at about 150 rpm. The resulting solution was filtered through acoffee filter to remove any particulate matter. The filtered solutionwas collected in a 50 mL Nessler color comparison tube. After 30minutes, each sample tube was visually examined for color (if any),clarity/turbidity, and if any noticeable difference in filtered solutionvolume exists (i.e., a significant decrease from the original 10 mLEtOH). The results for the whole and cut dosage units are provided inthe two tables below.

TABLE 13 Whole Dosage Unit Extraction Data Visual Examination-WholeDosage Units Color Color Notes (clarity/turbidity, Sample Sample NameChange Observed Intensity volume change, etc.) 1 Roxicodone ® 15 mg YesYellow Faint Clear, no volume change 2  IR 5 mg Yes Yellow Dark Clear,no volume change 3 IR 30 mg Yes Blue Medium Clear, ~1 mL volume decrease4 ER 10 mg Yes Blue Dark Clear, ~3 mL volume decrease 5 ER 80 mg YesGreen Dark Clear, ~4 mL volume decrease 6  Opana ® ER 5 mg No None NoneClear, no volume change 7 Opana ® ER 40 mg Yes Yellow Faint Clear, novolume change 8 Oxycontin ® 10 mg Yes White Faint Slightly turbid, novolume change 9 Oxycontin ® 40 mg Yes White Faint Slightly turbid, novolume change 10 Oxycontin ® 60 mg Yes Red Faint Slightly turbid, novolume change 11 Oxycontin ® 80 mg Yes Blue Faint Slightly turbid, novolume change

TABLE 14 Cut Dosage Unit Extraction Data Visual Examination-Cut DosageUnits Color Color Notes (clarity/turbidity, Sample Sample Name ChangeObserved Intensity volume change, etc.) 1 Roxicodone ® 15 mg Yes YellowFaint Clear, no volume change 2  IR 5 mg Yes Yellow Dark Clear, novolume change 3 IR 30 mg Yes Blue Medium Clear, ~1 mL volume decrease 4ER 10 mg Yes Blue Dark Clear, ~3 mL volume decrease 5 ER 80 mg Yes GreenDark Clear, ~4 mL volume decrease 6  Opana ® ER 5 mg No None None Clear,~1 mL volume decrease 7 Opana ® ER 40 mg Yes Yellow Faint Clear, ~1 mLvolume decrease 8 Oxycontin ® 10 mg Yes White Faint Slightly turbid, ~1mL volume decrease 9 Oxycontin ® 40 mg Yes White Medium Turbid, ~1 mLvolume decrease 10 Oxycontin ® 60 mg Yes Red Medium Turbid, ~2 mL volumedecrease 11 Oxycontin ® 80 mg Yes Blue Faint Turbid, slight volumechange

During filtration, samples passed through the filter at various rates.For example, samples 1 and 6-11 took approximately 20 seconds for theentire volume to completely pass through the coffee filter. Samples 2and 3 took approximately 15 minutes for the entire volume to completelypass through the coffee filter. Samples 4 and 5 took approximately 60minutes for the entire volume to completely pass through the coffeefilter. After filtration, samples 2-5 were uniform in color aftersitting for approximately 30 minutes, while samples 8-11 had significantsediment at the bottom of the comparison tubes. Samples 1, 6 and 7 hadno noticeable sediment but were significantly less colored than thebatches of the present disclosure.

Approximately 5 mL of the filtrate from each cut dosage form sample waspassed through a 25 mm, 0.2 μm PTFE Titan syringe filter (ScientificResources, Inc. Cat No. 42225-PC, Lot 709029003054). Each resultingsolution was then assigned a number according to a scale of 0-5, with 0(zero) representing a sample with no color and 5 representing a samplewith a dark, significant color, (0—no color; 1—faint; 2—light; 3—medium;4—brilliant; and 5—dark). Samples with at least light color, includingdark coloration, can deter potential abusers from injecting or ingestingthe filtered extract (e.g., colors 2 and above, 3 and above, 4 andabove, or 5). The table below shows the color number assignments for thesyringe filtered cut dosage unit solutions.

TABLE 15 Cut Dosage Unit Color Numbers Visual Examination-Cut DosageUnits Sample Number Sample Name Color 1 Roxicodone ® 15 mg 1 2  IR 5 mg5 3 IR 30 mg 3 4 ER 10 mg 5 5 ER 80 mg 5 6  Opana ® ER 5 mg 0 7 Opana ®ER 40 mg 1 8 Oxycontin ® 10 mg 0 9 Oxycontin ® 40 mg 0 10 Oxycontin ® 60mg 0 11 Oxycontin ® 80 mg 0

In some embodiments, the formulation of the present disclosureincorporates the dye throughout the entire dosage unit as opposed toincorporating the dye only in a coating. The dye can be water soluble,alcohol soluble or both. The dye can have a solubility in water, alcoholor both that is greater than about 0.01 g/100 mL, about 0.1 g/100 mL,about 1 g/100 mL or about 10 g/100 mL. Traditional drug formulation dyesare not soluble, or significantly soluble, in water, alcohol or both.They are often formulated into the coatings of the drug formulations. Insome embodiment, the dyes are water soluble, alcohol soluble or both,and are dyes that are approved for, or considered acceptable, for oraladministration. In some instances, the solubility of the dye in alcoholis important because of the potential for compounding effects of, andinteractions associated with, consuming both alcohol and the extractedAPI.

The following table lists the relative solubility of exemplarycomponents of a formulation. A number of different dyes are listed alongwith their solubility information taken from the various literaturesources and tested experimentally (200 proof ethanol and filteredthrough a 0.22 micrometer PTFE filter).

TABLE 16 General Solubility of Exemplary Components Alcohol AlcoholWater Solubility Solubility Exemplary Components Solubility (Literature)(tested) Oxycodone HCl Yes Yes N/A Polyethylene Oxide Yes No N/APolyethylene Glycol Yes Yes N/A Hydroxypropylmethylcellulose Yes No N/AMicrocrystalline Cellulose No No N/A Lactose Monohydrate Yes No N/A FD&CBlue #1 Yes Yes N/A FD&C Blue #2 Yes Yes Yes FD&C Yellow #5 Yes Yes YesFD&C Yellow #6 Yes Yes Yes FD&C Red #40 Yes Yes Yes Lake Dyes No No N/A

The sediment observed at the bottom of the comparison tubes of theOxycontin® batches (samples 8-11) is indicative of a suspension ratherthan a solution. Typically, suspensions can be centrifuged or filteredto obtain a more clear solution (and in some cases, a colorlesssolution). Conversely, solutions cannot be further centrifuged orfiltered using a common household coffee filter or a readily availablesyringe filter to obtain a more clear solution because the dye iscompletely dissolved in the solution. Dyed formulations can provide anadditional mechanism of abuse deterrence than coated formulations.

The amount of dye present in the formulation can be an amount thatproduces an extract or a filtered extract using water, alcohol or acombination of both with a color that is greater than 0, or greater than1, or greater than 2, or greater than 3 or greater than 4 on the visualscale disclosed, or similar scale. The amount of dye can vary dependingon the formulation and components present. In some embodiments, theformulation can contain at least 0.1% dye, at least 0.2% dye, at least0.3% dye, at least 0.4% dye, at least 0.5% dye, at least 0.6% dye, atleast 0.7% dye, at least 0.8% dye, at least 0.9% dye, at least 1.0% dye,at least 1.5% dye, at least 2.0%, or any range of these values (e.g.,between about 0.1% and about 1.0% dye).

It was also observed that a volume change occurred (˜3-4 mL decrease)for samples 4 and 5 following extended filtration time. Certainexcipients (e.g., hydroxypropylmethylcellulose) can cause the resultingsolution to become too viscous to fully pass through a coffee filter.Additional abuse deterrence (e.g., extended extraction time and volumeloss) can be obtained by formulations includinghydroxypropylmethylcellulose, or equivalents.

Additional Exemplary Formulations

Additional exemplary formulations of the present disclosure are providedin the tables below.

TABLE 17 Additional Exemplary Formulations Component 15 15 20 30 40 60Oxycodone HCl 15.00%  7.50% 10.00% 15.00% 20.00% 30.00% PEO, 100KDaltons 35.00% 40.00% 40.00% 40.00% 40.00% 40.00% MicrocrystallineCellulose PH 101 18.75% Lactose Monohydrate 316 17.65% Hypromellose,K100M 33.00% 31.00% 29.00% 29.00% 28.00% PEG, 8K Daltons 12.50% 17.50%17.85% 14.60%  9.25%  0.25% Citric Acid  1.00%  1.00%  1.00%  1.00% 1.00%  1.00% Dye  0.10%  1.00%  0.15%  0.40%  0.75%  0.75% Total weight100 mg 200 mg 200 mg 200 mg 200 mg 200 mg Release characteristics IR ERER ER ER ER

TABLE 18 Additional Exemplary Formulations Component Oxycodone HCl4.0-6.0% 28.0-32.0% 4.0-6.0% 32.0-35.0% PEO, 100K 33.0-37.0% 33.0-37.0%38.0-42.0% 38.0-42.0% Daltons Microcrystalline 21.0-24.0% 11.0-14.0%Cellulose PH 101 or or 15.0-35.0% 10.0-25.0% Lactose 19.0-23.0%10.0-15.0% Monohydrate 316 or or 15.0-35.0% 10.0-25.0% Hypromellose,36.0-39.0% 18.0-22.0% K100M PEG, 8K Daltons 13.0-17.0%  8.0-12.0%14.0-17.0% 4.0-6.0% Citric Acid 0.8-1.2% 0.8-1.2% 0.8-1.2% 0.8-1.2% Dye0.6-0.9% 0.05-0.2%  0.6-0.9% 0.8-1.2% or or or or 0.5-1.0% 0.05-0.5% 0.5-1.0% 0.5-1.5% Release IR IR ER ER characteristics

TABLE 19 Additional Exemplary Formulations Component Oxycodone HCl13.0-17.0%   6.0-9.0%  8.0-12.0% 13.0-17.0% 18.0-22.0% 28.0-32.0% PEO,100K Daltons 33.0-37.0% 38.0-42.0% 38.0-42.0% 38.0-42.0% 38.0-42.0%38.0-42.0% Microcrystalline 17.0-20.0% Cellulose PH 101 or 15.0-35.0%Lactose Mono- 16.0-19.0% hydrate 316 or 15.0-35.0% Hypromellose, K100M31.0-35.0% 29.0-33.0% 27.0-31.0% 27.0-31.0% 26.0-30.0% PEG, 8K Daltons11.0-14.0% 16.0-19.0% 16.0-19.0% 13.0-16.0%  8.0-11.0%   0.2-0.3% CitricAcid   0.8-1.2%   0.8-1.2%   0.8-1.2%   0.8-1.2%   0.8-1.2%   0.8-1.2%Dye  0.05-0.2%   0.8-1.2%   0.1-0.3%   0.3-0.5%   0.6-0.9%   0.6-0.9% oror or or or or  0.05-0.5% 0.75-1.25%   0.1-0.5%   0.3-0.8%   0.5-1.0%  0.5-1.0% Release characteristics IR ER ER ER ER ER

Cutting Force Example

The existing methodology used to evaluate abuse deterrence in regard tothe cutting or breaking of a dosage form is based on the USP's “tabletbreaking force” test. This test defines “tablet breaking force” as theforce required to cause tablets to fail (i.e., break) in a specificplane. The USP describes the test as follows “[t]he tablets aregenerally placed between two platens, one of which moves to applysufficient force to the tablet to cause fracture. The platens should beparallel. Their faces should be polished smooth and precision-groundperpendicularly to the direction of movement. Perpendicularity must bepreserved during platen movement, and the mechanism should be free ofany bending or torsion displacements as the load is applied. The contactfaces must be larger than the area of contact with the tablet.” FIG. 6shows equipment capable of executing traditional “tablet breaking force”analysis.

The USP further explains the applications of tablet breaking force andwhy it is utilized in the industry. “Tablets must be able to withstandthe rigors of handling and transportation experienced in themanufacturing plant, in the drug distribution system, and in the fieldat the hands of the end users (patients/consumers). Manufacturingprocesses such as coating, packaging, and printing can involveconsiderable stresses, which the tablets must be able to withstand. Forthese reasons, the mechanical strength of tablets is of considerableimportance and is routinely measured.” The intent of these applicationsis for traditional formulations which may be subjected to forces whichcould break the tablets (i.e., vigorous shaking in a tablet bottle). Theintent is not to address abuse deterrence potential. Furthermore, thistest is only applicable to and instructive to evaluate tabletformulations. The test is not applicable to or instructive to evaluatepill, or other formulations, prepared by extrusion methodologies.

In formulations utilizing excipients such as polyethylene oxide, andusing such excipients in an extrusion process, the parameter “tabletbreaking force” does not apply. For example, the long molecular chainlengths of the PEO (e.g., 100,000 Daltons-7,000,000 Daltons) cause thedrug product (relative to other traditional drug products) to beflattened, but never actually “fail” (i.e., break) when applying “tabletbreaking force” in the traditional sense. The traditional application of“tablet breaking force” needs to be modified to evaluate formulationscontaining malleable excipients (such as PEO) for the “cutting force” ofthe dosage form, specifically dosage forms which are intended to deterabuse. The modification of the traditional “tablet breaking force” testpresented in this study consists of a change from the “platens” utilizedto cause the dosage forms to “fail” (i.e., break), namely from contactfaces “larger than the area of contact with the tablet” to sharp planeswhich mimic commonly used tools for abuse. FIGS. 7, 8 and 9 showreference attachments including a fracture wedge set (used to mimiccommon kitchen scissors, FIGS. 7 and 8 showing different views of thesame set) and a razor blade (FIG. 9).

The purpose of this study is to perform and summarize the cutting forceneeded to cut different formulations of CII narcotic drug products.Texture analysis is the mechanical testing of pharmaceutical products inorder to measure their physical properties. A Texture Analyzer XT2i canperform testing of numerous physical properties of pharmaceuticalproducts, including cutting force. The cutting force needed to cutseveral different formulations of CII narcotic drug products utilizingdifferent attachments on a Texture Analyzer (TE37) was investigated.Multiple tools were utilized to cut drug products with the intent ofabuse including two attachments which mimic readily available tools usedfor abuse (e.g., a razor blade and kitchen scissors). The cutting forcefor all evaluated drug products were evaluated with each attachment.

Experimental

The samples tested include those samples listed in Table A. Theformulations of the samples of the present disclosure tested are listedin Table B. The Texture Analyzer (TE37), Model XT2i HR was operated atthe following conditions: Pre Test Speed: lmm/s; Test Speed: 0.25 mm/s;Post Test Speed: 10 mm/s; Distance: 99.9% (% Strain); Trigger Type: Auto(Force=0.2N) and Break Detect: Off. A sample size of N=10 was used foreach sample per cutting attachment. The cutting force results of the CIInarcotic drug products utilizing both cutting attachments (razor bladeand fracture wedge set) was determined. FIGS. 10A and 10B show thecutting force data tables for the razor blade and the fracture wedgeset.

The individual maximum cutting force needed to cut any tested CIInarcotic drug products utilizing the razor blade was 142N (sample 7).The highest average cutting force needed to cut any tested CII narcoticdrug products utilizing the razor blade was 131N (sample 7). Theindividual maximum cutting force needed to cut any tested CII narcoticdrug products utilizing the fracture wedge set was 163N (sample 6). Thehighest average cutting force needed to cut any tested CII narcotic drugproducts utilizing the fracture wedge set was 156N (sample 6).

All of the tested CII narcotic drug products can indeed be cut, andtherefore potentially be abused, with force which is substantially lowerthan what has been reported using the breaking strength test orequivalent (>500N, See U.S. Pat. No. 8,309,060) utilizing conventionalmeans (i.e., common kitchen scissors or a razor blade). “Flattening” thetablets utilizing forces >500N (with traditional “tablet breaking force”definitions) does not address abuse deterrence potential in the testedCII narcotic drug products.

In one embodiment, the formulation of the present invention exhibits acutting strength (i.e., force needed to cut the formulation) of greaterthan about 40 N, about 50 N, about 60 N, about 70 N, about 80 N, about90 N, about 100 N, about 110 N, about 120 N, or about 130 N, or anyrange of these values (e.g., between about 40 N and about 120 N), astested by either the Cutting Force—Razor Blade test or by the CuttingForce—Fracture Wedge Set test, or both.

Samples 4 of 5 of the present disclosure exhibit improved cuttingstrength compared to the compress-and-cure samples (i.e., samples 8-11).Samples prepared via a compress-and-cure procedure undergo dry mixing ofthe components only. These components are then compressed into a dosageform, and placing on a drying pan which applies heat to the dosage form.It is believed that compress-and-cure dosage forms are not melted orsimilarly liquefied to create significant homogeneity within the dosageform as compared to extrusion based procedures. The dosage formulationsof the present invention are prepared by extrusion and, therefore,possess significant homogeneity as a result of the extrudate mixingwithin the extruder under melt flow conditions. The extrudateexperiences high shear forces that produce the mechanical energy neededto ensure the required hardness and strength are achieved. The highshear forces can act on select components, for example PEO, to transformthem into networks that exhibit increased strength and stability.

Grinding Example

The purpose of this study is to perform and summarize the grindingpotential of different formulations of CII narcotic drug products.Texture analysis is the mechanical testing of pharmaceutical products inorder to measure their physical properties. The Retsch Knife MillGRINDOMIX GM200 (TE96) was utilized to mimic a commercially availablecoffee grinder (Mr. Coffee) in order to grind CII drug products into aparticle size that is suitable for intranasal abuse (insufflation). Acommercially available coffee grinder was also evaluated for comparisonpurposes. Particle size analysis was conducted utilizing an ATM L3PSonic Sifter (TE47), utilizing a 500 micrometer (μm) particle size sieve(35 mesh). For the purposes of this study, any particle less than 500 μmin diameter is considered suitable for intranasal abuse. It is generallyaccepted as an industry standard that any particle greater than 500 μmin diameter cannot be sufficiently absorbed by the blood vessels in thenasal passages.

The Retsch Knife Mill GRINDOMIX GM200 utilizes a circular bladeattachment to mimic commercially available coffee grinders. The GM200has a top speed of 10,000 revolutions per minute (rpm), whilecommercially available coffee grinders have a top speed of approximately20,000 rpm (an approximate two-fold increase in speed when comparing theGM200 to a Mr. Coffee grinder). However, the approximate two-foldincrease in blade diameter (118 mm vs. 60 mm, when comparing the GM200to a Mr. Coffee grinder, respectively) compensates for the approximatetwofold decrease in top speed via the inversely proportionalrelationship of the two variables. Further, the torque provided by theGM200 is significantly higher than the torque provided by a Mr. Coffeegrinder (0.860 Nm (Newton meters) of the GM200 vs. 0.062 Nm of the Mr.Coffee grinder, respectively), which additionally illustrates theability (or lack thereof) of the Mr. Coffee grinder to modify the drugproducts into a particle size suitable for intranasal abuse. The studyevaluated the difference in particle sizes of several differentformulations of CII narcotic drug products following modification(grinding) by the GM200 and Mr. Coffee grinder.

Additionally, a non ADF drug product which utilizes traditionalcompression manufacturing methods (Roxicodone® 15 mg, manufactured byMallinckrodt, Inc.) was evaluated for comparison purposes.

Experimental: The samples tested include those samples listed in TableA. The formulations of the samples of the present disclosure tested arelisted in Table B. The following test equipment was used: Retsch KnifeMill GRINDOMIX GM200 (TE96), Coffee Grinder (Mr. Coffee), ATM L3P SonicSifter (TE47), 500 μm sieve (35 mesh) and a Shimpo InstrumentsTachometer (TE31). The following testing conditions were used: Analysisspeed: 10,000 rpm (GM200), 20,000 rpm (Mr. Coffee); Analysis time: 30seconds; Sieve Size: 500 μm (35 mesh); Analysis time: 2 minutes (nopulse). Each sample was prepared in triplicate (N=3).

For each sample, three (3) dosage units were weighed and tested. Thefollowing conditions were used with the TE96: a 30 second analysis timeand a speed of 10,000 rpm. Both parameters were set prior to eachanalysis. The composite sample was transferred to a tared weigh boat andthe weight of the sample was recorded. The following equation was usedto calculate the % sample loss:

${{Sample}\mspace{14mu} {Loss}\mspace{14mu} (\%)} = {100 - \left( {\frac{{Analyzed}\mspace{14mu} {Sample}\mspace{14mu} ({mg})}{{Sample}\mspace{14mu} {Weight}\mspace{14mu} ({mg})} \times 100} \right)}$

The weight of the 35 mesh sieve and sample pan was recorded. The testingapparatus was assembled with the 35 mesh sieve above the sample pan. Thecomposite sample was transferred to the testing apparatus and analyzedutilizing the following parameters: 2 minute analysis time and no pulse.The analyzed 35 mesh sieve and sample pan were weighed. The % materialremaining on the 35 mesh sieve (≥500 μm) and in the sample pan (≤500 μm)was calculated using the following equation:

${{Percent}\mspace{14mu} {on}\mspace{14mu} {Sieve}\mspace{14mu} (\%)} = {\frac{{Weight}\mspace{14mu} {of}\mspace{14mu} {Sample}\mspace{14mu} {on}\mspace{14mu} {Sieve}\mspace{14mu} ({mg})}{{Total}\mspace{14mu} {Weight}\mspace{14mu} {of}\mspace{14mu} {Sample}\mspace{14mu} {on}\mspace{14mu} {Sieve}\mspace{14mu} ({mg})} \times 100}$

The procedure was repeated for the Mr. Coffee grinder in place of theTE96. The Mr. Coffee grinder has 1 operating speed (˜20,000 rpm). Theparticle size analysis and grinding results are shown in FIGS. 11A, 11B,and 12A-12F.

FIG. 14 shows a representation of particle size results (%≥500 μm) whencomparing the tested Immediate Release (IR) Roxicodone® batch vs. theformulations of the present disclosure (e.g., IR batches) utilizing bothTE96 and the Mr. Coffee grinder.

FIG. 15 shows a representation of particle size results (%≥500 μm) whencomparing the tested Extended Release (ER) CII narcotic drug productsbetween manufacturers.

The Roxicodone® batch provides statistically different (lower) amountsof particles ≥500 μm than the formulations of the present disclosure(e.g., IR samples) following grinding and particle size analysis.Statistical significance was tested against a 95% confidence interval ora p-value of less than 0.05. Combined Oxycontin® batches providestatistically different (lower) amounts of particles ≥500 μm thancombined formulations of the present disclosure (e.g., ER samples andcombined Opana® batches following grinding and particle size analysis asdescribed in the protocol.

The results were combined per manufacturer, i.e. the present disclosure,Opana® ER batch results, and Oxycontin® results, and analyzed as groups.The combined Opana® batches provide statistically similar amounts ofparticles ≥500 μm as the combined formulations of the present disclosure(e.g., ER samples) following grinding and particle size analysis.

Example 4

Abuse deterrent formulations were prepared containing both a dye and analcohol purity decreasing agent. Table 20 shows an exemplaryformulation.

TABLE 20 Exemplary Abuse Deterrent Formulation Ranges Components Wt % Wt% Wt % Active 3.0-7.0 13.0-17.0  28.0-32.00 Matrix 33.0-37.0 33.0-37.033.0-37.0 Plasticizer 20.0-25.0 15.0-20.0  8.0-12.0 Filler20.0-25.020.0-25.0 15.0-20.0  8.0-12.0 Purity Decreasing Agent  8.0-12.0 8.0-12.0  8.0-12.0 Preservative 0.5-2.0 0.5-2.0 0.5-2.0 Dye 2.0-6.02.0-6.0 2.0-6.0

TABLE 21 Exemplary Abuse Deterrent Formulation for 100 mg IR pill 100 mgIR Pill 5 15 30 Components Wt % Wt % Wt % Oxycodone Hydrochloride(active) 5.0 15.0 30.0 Sentry PolyOX WSR N-10 LEO, NF (matrix, e.g.,35.0 35.0 35.0 PEO) Carbowax Sentry Polyethylene Glycol 8000 Powder,22.5 17.5 10.0 NF (plasticizer) Lactose Monohydrate 316L FastFlo(filler) 22.5 17.5 10.0 Calcium Acetate, USP (purity decreasing agent)10.0 10.0 10.0 Citric Acid, Anhydrous Fine Ganular, USP 1.0 1.0 1.0(preservative) Coloron Red Dye Blend (dye) 4.0 4.0 4.0

The exemplary formulation in Example 4 was tested for dissolution,purity before and after extraction, and evaluated for the effectivenessof the dye. The dissolution and dye tests are described above in thepreceding examples. The extraction test is described below. FIG. 13shows the test results. The formulation passed dissolution testing. Theformulation showed a decrease in purity after extraction in alcohol. Itis noted that the formulation showed significant color after filtrationwith using about 4 wt % dye. Prior to filtering, the solutions werecolored as a result of the dye being present in the formulation. Ingeneral, filtering the solution with a syringe filter did notsubstantially reduce the color of the filtrate. For nylon filters,however, a substantial reduction in color was observed. It is believedthat nylon has an affinity to the dye used in the formulation. As aresult, in some embodiments, a sufficient amount of dye is added tosaturate any filter (e.g., a nylon filter) used to filter the solutionand also to allow the filtrate to be colored (e.g., at least 1 wt % dye,at least 2 wt % dye, at least 3% dye, etc.).”

Extraction Procedure for ADF IR Extruded Pills

The extraction procedure involves testing the resultant purity of anextract using alcohol and/or water as the extraction solvent. Here, fourwhole ADF 30 mg IR pills were placed in a 125 mL Erlenmeyer flask. 40.0mL of 190-proof ethanol (95%) was pipetted into the flask. The flask wassealed and allowed to shake overnight on a platform shaker(concentration of stock solution=3 mg/mL oxycodone HCl).

This procedure was repeated utilizing water as the extraction solvent.

After approximately 12 hours, both flasks were removed from the platformshaker. A portion was filtered through a 0.45 μm nylon syringe filterinto a 10 mL glass beaker. 5.0 mL of this solution was pipetted into a150 mL beaker and heated on a hot plate at ˜100° C. (theoretically 15 mgof oxycodone HCl powder in solution). The heat was continuously addeduntil each solution evaporated. Both beakers were allowed to cool toroom temperature and then scraped with a metal spatula. The resultingpowder was weighed and subsequently prepared for chromatographicanalysis.

Each sample was weight corrected and analyzed for assay purity ofoxycodone HCl.

The assay purity is the percentage of oxycodone HCl in the extractedpowder. As the assay purity of oxycodone HCl decreases the amount ofextracted powder necessary to achieve higher oxycodone HCl contentincreases. Additionally, as the assay purity of oxycodone HCl decreases,the excipient load present in the extracted powder increases. Therefore,it can be concluded that drug products which provide, upon ethanol orwater extraction, a lower assay purity of oxycodone HCl in extractedpowder are abuse deterrent. This deterrence is evident in the followingways: cost effectiveness (i.e., the need for more powder to produce anequivalent amount of oxycodone HCl); time effectiveness (i.e., a powderof lower purity containing oxycodone HCl which cannot be separated fromthe excipients without complex, time-consuming chemistry procedures);and the potential for introducing a higher excipient load into the body.

While this disclosure has been particularly shown and described withreference to example embodiments thereof, it will be understood by thoseskilled in the art that various changes in form and details may be madetherein without departing from the scope of the invention encompassed bythe appended claims.

1. A directly-formed oral, immediate release, abuse deterrent dosageform comprising an active substance susceptible to abuse, a matrix agentand a plasticizer, wherein the dosage form is directly formed from anextrusion process. 2-3. (canceled)
 4. An oral, immediate release, abusedeterrent dosage form comprising: (i) an active substance susceptible toabuse; (ii) a matrix agent, wherein the matrix agent has an averagemolecular weight between about 50K Daltons and 300K Daltons; and (iii) aplasticizer, wherein the active substance susceptible to abuse has animmediate release profile, and wherein the composition includes aphysical barrier to reduce abuse.
 5. The oral, immediate release, abusedeterrent pill of claim 4, wherein the active substance is Oxycodone HClor Hydrocodone Bitartrate.
 6. The oral, immediate release, abusedeterrent pill of claim 4, wherein the physical barrier reduces abuse bypulverizing and swallowing, pulverizing and snorting, or pulverizing andinjecting.
 7. The oral, immediate release, abuse deterrent pill of claim4, wherein the physical barrier is the pill has at least 50 Wt % ofparticles with a particle size greater than 0.5 mm following physical ormechanical manipulation of the pill.
 8. The oral, immediate release,abuse deterrent pill of claim 4, wherein the physical or mechanicalmanipulation includes pulverizing, cutting, grating or grinding.
 9. Theoral, immediate release, abuse deterrent pill of claim 4, wherein thephysical barrier is the pill forms a hydrogel upon exposure to anaqueous solution.
 10. The oral, immediate release, abuse deterrent pillof claim 4, wherein the matrix agent is selected from the groupconsisting of agar, alamic acid, alginic acid, carmellose,carboxymethylcellulose sodium, chitosan, copovidone, dextrin, gelatin,hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose (HPMC),methylcellulose derivatives, microcrystalline cellulose, polyacrylicacid, polyalkalene oxide, polyvinyl acetate, polyvinyl alcohol,povidone, propylene glycol alginate, a polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft co-polymer, pullulan, silicon dioxide,sodium alginate, starch, and vinylpyrrolidone-vinyl acetate copolymers.11. The oral, immediate release, abuse deterrent pill of claim 4,wherein the pill contains about 10 Wt % to about 90 Wt % of matrixagent.
 12. The oral, immediate release, abuse deterrent pill of claim 4,wherein the plasticizer is selected from the group consisting ofpolyalkalene glycol, acetyltributyl citrate, acetyltriethyl citrate,castor oil, diacetylated monoglycerides, dibutyl sebacate, diethylphthalate, glycerin, propylene glycol, pullulan, sorbitol sorbitansolution, triacetin, tributyl citrate and triethyl citrate.
 13. Theoral, immediate release, abuse deterrent pill of claim 4, wherein thepill contains about 5 Wt % to about 60 Wt % of plasticizer.
 14. Theoral, immediate release, abuse deterrent pill of claim 4, furthercomprising a filler, a disintegrant, or an alcohol purity decreasingagent. 15-17. (canceled)
 18. The oral, immediate release, abusedeterrent pill of claim 4, further comprising a FD&C dye.
 19. The oral,immediate release, abuse deterrent pill of claim 4, wherein greater thanor equal to 75 Wt % of the active substance is released from the pillwithin 45 minutes following administration.
 20. An oral, immediaterelease, abuse deterrent dosage form comprising: (i) about 0.5 Wt % toabout 30 Wt % of an active substance susceptible to abuse; (ii) about 10Wt % to about 90 Wt % of a matrix agent having an average molecularweight of about 50K Daltons to about 300K Daltons; and (iii) about 5 Wt% to about 60 Wt % of a plasticizer. 21-26. (canceled)
 27. An oral,immediate release, abuse deterrent dosage form comprising an activesubstance susceptible to abuse, wherein less than about 95% of theactive substance is released from the dosage form within 20 minutesfollowing administration, and wherein greater than or equal to 75% ofthe active substance is released from the dosage form within 45 minutesfollowing administration.
 28. A process for the production of an oral,immediate release, abuse deterrent dosage form containing at least oneactive substance susceptible to abuse comprising: (i) processing auniform blend of the at least one active substance susceptible to abuse,a matrix agent and a plasticizer by hot melt extrusion using an extruderto make an extrudate; and (ii) forming the extrudate using a formingunit into the dosage form. 29-34. (canceled)
 35. A process for theproduction of an oral, immediate release, abuse deterrent dosage form,comprising: (i) processing an analytically determined uniform blend ofat least one active substance susceptible to abuse, a matrix agent and aplasticizer by hot melt extrusion using an extruder to make an extrudateand forming the dosage form. 36-37. (canceled)
 38. A process for theproduction of an oral, immediate release, abuse deterrent pillcontaining at least one active substance susceptible to abusecomprising: (i) combining the at least one active substance susceptibleto abuse, a matrix agent and a plasticizer in a hopper to form amixture; (ii) blending the mixture in the hopper until a uniform blendis achieved; (iii) monitoring the mixture during blending using aprocess analytical technique to determine when a uniform blend isachieved; (iv) feeding the uniform blend into an extruder; (v)processing the uniform blend by hot melt extrusion in the extruder tomake an extrudate; (vi) transferring the extrudate to a forming unitusing a transfer unit capable of controlling the temperature, pressure,environment or shape of the extrudate; (vii) forming the extrudate usingthe forming unit into the pill; and (viii) determining the quality,volume and weight of the pill using an optical inspection technique. 39.A method of treating pain comprising administering to an individual inneed thereof a therapeutically effective amount of a dosage form ofclaim 1.